Sports Med 2009; 39 (5): 339-344 0112-1642/09/0005-0339/$49.95/0
CURRENT OPINION
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Genetic Testing and Sports Medicine Ethics Michael John McNamee,1 Arno Mu¨ller,2 Ivo van Hilvoorde3 and Søren Holm4 1 Department of Philosophy, History and Law, School of Health Science, Swansea University, Swansea, UK 2 Maastricht University, Department of Health, Ethics and Society, Maastricht, the Netherlands 3 Research Institute MOVE, Faculty of Human Movement Sciences, VU University Amsterdam, Amsterdam, the Netherlands 4 Cardiff Law School, Cardiff University Law Building, Museum Avenue, Cardiff, UK
Abstract
Sports medicine ethics is neither a well established branch of sports medicine nor of medical ethics. It is therefore important to raise to more general awareness some of the significant ethical implications of sports medicine practices. The field of genetics in sports is likewise in its infancy and raises significant ethical concerns. It is not yet clear how genetics will alter our understanding of human potential and performance in sports. While a number of professional medical bodies accept genetic interventions of a therapeutic nature, we argue that the use of genetic technologies to predict sports potential may well breach both the European bioethics convention and North American anti-discrimination legislation, which are designed to support important ethical ideals and the ongoing commitment of the physician to the welfare of their patient. We highlight further ethical problems associated with confidentiality and consent that may arise in genetic testing as opposed to more conventional methods of testing in sports medicine. We conclude that genetic testing in sport that is not strictly limited to the protection of the athlete against harm, should be viewed in a very sceptical light by sports medicine professionals.
With the particular exception of doping, the emerging field of sports medicine ethics has attracted relatively little ethical discussion compared with more established branches of medicine. Recently, commercial,[1,2] professional and scientific discussions of genetics have raised the possibility of genetic testing for sports performance prediction[3-7] in addition to preventative and therapeutic purposes.[6-8] We note the powerful case that can be made for genetic testing regarding the identification of predisposition to hypertrophic cardiomyopathy.[9-13] However, in contrast, we
raise key ethical issues that reveal a conflict between common employment practice and professional sport from within the more established fields of medical ethics and legislation. Genetic testing for predictive purposes such as talent identification or performance profiling is potentially in breach of the Council of Europe Bioethics Convention[14] and the Genetic Information Non-Discrimination Act in the US.[15] Given the economic and power asymmetry between professional sports franchises and individual professional athletes, we argue that the voluntary
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consenting to genetic testing may be undermined and that duress or even coercion may be used to secure the data that can be acquired through genetic testing. Moreover, even if acceptance is secured under voluntary conditions it is necessary to consider the degree of comprehension and thus the ‘informedness’ of athletes of the consent. Finally, if genetic testing is to develop in sports medicine, we highlight the need for acceptable and available systems for genetic counselling before and after testing.[7] We conclude that genetic testing in sport, which is not strictly limited to the protection of the athletes against harm, should be viewed in a very sceptical light by sports medicine professionals. While sports ethics as a research field is in its infancy, sports medicine ethics can only be classified as neonatal. Very few articles exist that attempt to lay down the boundaries of what is a potentially important research field.[16,17] The conflicts of interests between team doctors in relation to their employing sports franchises and other governing bodies such as the National Basketball Association or the National Football League and their long-term commitment to the health and well-being of their athlete patient are relatively well known[18] but rarely scrutinized from an ethical point of view. The advent of genetic medicine in general and genetic testing in sports medicine brings new ethical issues to light that merit critical ethical scrutiny. It is not yet clear precisely how genetics will alter our understanding of athletic potential and performance.[19,20] Some of the claims made by sports ethicists and scientists regarding the potential for human enhancement seem to blur the lines between fact and science fiction.[3,21] In addition to these problems, a fairly recent article neglects even to mention professional athletics and sports medicine in its review of ethical, legal and social implications of genetic medicine.[22] Whether or not we accept the enhancement scenarios, some research has established some important genetic precursors to athletic development especially regarding muscular contraction and growth. However, little comment has been made concerning the preventive application of genetic testing in sports as well as of the ethical ª 2009 Adis Data Information BV. All rights reserved.
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implications for sports medicine. This article raises a number of interrelated ethical issues that affect sports medicine in relation to professional athletes.
1. Genetic Testing for Prevention or (Sports) Performance? Recently both popular and scientific discussion has raised the possibility of genetic testing for sports performance prediction. The following is indicative: ‘‘Many of the variables that determine athletic performance are partially inherited (Spurway, 2007) and therefore one can foresee the use of genetic tests to predict performance.’’[3] Beyond biomedical science, some bioethicists have also made similar claims as to its potential uses,[4-7] while others, ourselves included, are more sceptical.[8] The potential of sports genetics is often based on the claim that a single gene (ACTN3) is crucially related to sports performance potential.[23] This is based on its expression in type II (fast twitch) muscle fibres, which are of importance to sports where speed is integral. There are even commercially available test kits[1,2] for the most eager of sports parents or youth sports coaches with talent identification (and its economic and social benefits) in mind. The discovery of ACTN3 apparently ‘‘marks the beginning of a new era.’’[3] What is to be made of such a grand claim? The first is that perhaps the attraction of citing such an important genetic contributor is so great that some are prepared to leap precipitously to claim that without ACTN3 there is no quick muscle contraction. However, a recent single case report of a Spanish doubleOlympic, world-class long jumper has shown that his achievements were notable because of a deficient ACTN3 gene.[24] We would be mistaken if we tried to reduce complex traits such as muscle power and speed down to a single gene.[25] Therefore, a precautionary approach might be wiser until the evidence is supported more widely about the function of ACTN3. However, a recent analysis of commercial genetic profiling for health risks and interventions suggests: Sports Med 2009; 39 (5)
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‘‘Although genomic profiling may have potential to enhance the effectiveness and efficiency of preventive interventions, to date the scientific evidence for most associations between genetic variants and disease risk is insufficient to support useful applications.’’[26] Given that genomic medicine and technology are advancing so rapidly, it is worth considering their potential ethical impact in advance of actual medical applications in athletics.[6] Although in several cases healthcare practitioners are powerless to prevent or treat certain conditions after the realization of a (genotype) positive test result, genetic testing for athletes might enable physicians to prevent individuals who are not aware of their health condition from dying a death triggered by sports, as in the case of hypertrophic cardiomyopathy.[9-13] Currently, the health-related use of genetic testing in sport (i.e. in preparticipation examinations) is not a standard procedure. It is recommended by some cardiologists in borderline cases (ambiguous ECG/echo, borderline wall thickness). Pigozzi and Rizzo state that ‘‘if certain diagnosis is not possible but the suspect of disease is high, the most definitive evidence for the presence of hypertrophic cardiomyopathy (HCM) comes from DNA analysis.’’[27] If, however, a family member is diagnosed with hypertrophic cardiomyopathy, then, despite lack of symptoms, a genetic screening of the entire family should be considered.[28] On the other hand, genetic testing is mandatory when definitive diagnosis for genotype-related risk stratification and therapy is required, as can be the case in athletes with long QT syndrome (LQTS).[11] Regarding LQTS, the Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group sounds caution by stating that ‘‘genetic testing is not recommended for diagnosis of uncertain or ‘borderline’ congenital LQTS outside the setting of expert clinical and detailed family assessment.’’[29] Not all diseases are monocausal, which obviously reduces the predictive quality of such tests, not to mention the high costs as a consequence of testing a whole range of genes that are suspected to be linked to a certain disease. These obstacles (among others) lead to the conª 2009 Adis Data Information BV. All rights reserved.
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clusion that genetic tests are probably not becoming a standard in preparticipation screenings, at least not in the near future. 2. Genetic Testing in Sports and the Legal Regulation of Genetic Testing in Employment Suppose that athletic predestination is reliably predictable by new genetic sports medicine at some point in the near future. What will follow from this? What is scientifically possible and what is ethically permissible do not always go hand in hand. One very significant barrier to this use of genetics already exists in Europe in the form of the Council of Europe Bioethics Convention where Article 12 regarding predictive genetic tests states: ‘‘Tests which are predictive of genetic diseases or which serve either to identify the subject as a carrier of a gene responsible for a disease or to detect a genetic predisposition or susceptibility to a disease may be performed only for health purposes or for scientific research linked to health purposes, and subject to appropriate genetic counselling.’’[14] Here, the idea of someone undergoing genetic testing in order to establish some kind of performance profile would itself go against the strict therapeutic or preventative rationale of the Council of Europe Convention. Also, in the US the Genetic Information Non-Discrimination Act of 2008 Section 202a explicitly prohibits the use of genetic information in employment decisions.[15] There are further obstacles to genetic testing for sports performance arising from this Convention that raise ethical issues to be addressed beyond European confines, which we address below. For the moment, it is important to note one important difference between genetic testing in public health and in professional sports. However, as noted above, where healthcare practitioners are incapable of therapeutic interventions, the testing is still not futile given the possibility of identifying susceptibility to HCM.[9-13] Equally, this may cause problems since genetic data revealed about a given athlete may be disclosed to public bodies such as the World Anti-Doping Sports Med 2009; 39 (5)
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Agency and in so doing the privacy of data of relatives will be denied.[6,7] Nevertheless, just because it may be impossible to cure a patient of a given condition, it does not follow that genetic testing is redundant. However ‘‘DNA-based diagnostic tests that can definitively distinguish genetic heart diseases from athlete’s heart’’[13] could genuinely save lives. Moreover, genetic testing for APOE4 in addition to traditional screening has been used voluntarily in Australia with boxers who are vulnerable to early onset of Alzheimer’s disease if they have the gene.[4,30,31] Our point is not against genetic testing in sports per se, but merely against the questionable validity of genetic prediction of sports performance and the expansion of its role beyond traditional preventative and therapeutic aims. While it is clear that the boundary between the traditional curative goals of medicine and the more novel enhancement aims of sports medicine is not absolute, the distinction still remains a useful one.
3. Problems of Confidentiality and Consent in Professional Sports Medicine In highly paid professional sports, what are the possible scenarios in offering a test for a sports-related risk factor? Can the asymmetry of power between franchise and player be made worse by genetic knowledge? If consent procedures are properly followed, the ability to volunteer might still be in question: how does the sports physician present the case for and against, under what circumstances and with what preconditions? Even if this process was followed in an ethically acceptable manner, what steps should follow from different test results. Testing itself does not guarantee objective and unequivocal prognoses: nor does the genetic counselling, which would need to follow.[7,32] Human interpretation and valuation of risk factors are still necessary. How are the test results presented, by whom and under what conditions? What does a certain risk mean in one context, compared with another? All these issues will require serious public professional debate if genetic testing is to gain a foothold in sports medicine. ª 2009 Adis Data Information BV. All rights reserved.
Moreover, while respect for patient autonomy is often regarded as the crucible of medical ethics,[33] concerns arise from the very nature of genetic data presented under the heading ‘genetic exceptionalism’.[34] For example, Yesley[35] disputes the claims to the uniqueness of genetic data as opposed to other forms of traditional screening and testing. Given, however, the complexity of issues surrounding genetic data, what confidence is justified regarding professional athletes’ capacity to grasp fully the decision to be genetically tested? A further problem arises regarding confidentiality: with whom will the genetic data be shared? Will existing pressures on team doctors to divulge athlete/patient information[16] be exacerbated? Often the physiotherapist or team doctor find themselves caught in a conflict of interest. They serve both the athlete/patient and the franchise/client who pay their wages. The data they have regarding the health and performance status are highly sensitive but in great demand from the employing franchise, the coach and potential commercial suitors. Genetic testing in employment for anything other than health risk related to the specific job is generally frowned upon. Why should professional sports differ? Article 12 of the European Convention prohibits the use of predictive tests for non-health-related reasons, even with the assent of the patient. Predictive genetic testing as part of pre-employment medical examinations is forbidden whenever it does not serve the healthrelated interests of the individual. This means that in particular circumstances, when the working environment could have prejudicial consequences on the health of an individual because of a genetic predisposition, predictive genetic testing may be offered without prejudice with the aim of improving working conditions. Which genetic anomalies are deleterious to given athletes in specific sports? Should sports employers be allowed to hire and fire based on unexpressed genetic abnormalities? How should the athlete’s right not to know other deleterious conditions be respected? There is a justifiable requirement to carry out performance tests to judge, for example, the effort of the athlete, or their adherence and commitment to a specified training Sports Med 2009; 39 (5)
Genetic Testing and Sports Medicine Ethics
regimen in order to decide whether to offer or extend a professional contract. This does not, however, justify a ‘fishing expedition’ of potentially wide-ranging personal genetic data. 4. Conclusions We have attempted to raise critical questions regarding the potential of genetic testing in sports medicine without rejecting it tout court. We recognize that if genetic testing is carried out for enhancement purposes it may have the unintended, but desirable, consequence of highlighting potentially harmful diseases or conditions that may be exacerbated by high-level athletic activity. Nevertheless, we have cast doubt on the possibility of sports performance prediction, but have also raised key ethical issues where there is a clash between common employment practice and sport and mainstream medical ethics and law. Given the economic asymmetry between the commercial sports franchise and the individual professional athlete, we have shown that genetic testing in sport that is not strictly limited to the protection of the athlete against harm should be viewed in a very sceptical light by sports medicine professionals. Acknowledgements Dr Arno Mu¨ller’s research project ‘Sports, Ethics and Genomics’ at Maastricht University, Maastricht, the Netherlands, Department Health, Ethics and Society is funded by the Centre for Society and Genomics (CSG). The CSG is a centre of excellence of the Netherlands Genomics Initiative (NGI).
References 1. Genetic Technologies. Sports Performance ACTN3 Sports Gene Test 2006 [online]. Available from URL: http:// www.gtg.com.au/archives/migration/2/110/383/ACTN3% 20web%20brochure.pdf [Accessed 2009 Feb 27] 2. The Human Genetics Society of Australasia. HGSA position statement on genetic testing and sport performance. Alexandria: The Human Genetics Society of Australasia, 2007 3. Williams AG, Wackerhage H, Miah A, et al. Genetic research and testing in sport and exercise science: British Association of Sport and Exercise Sciences position stand [online]. Available from URL: http://www.bases.org.uk/ newsite/pdf/BASES [Accessed 2007 Sep 15]
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4. Savulescu J, Foddy B. Comment: genetic test available for sports performance. Br J Sports Med 2005 Aug 1; 39 (8): 472 5. Miah A, Rich E. Genetic tests for ability? Talent identification and the value of an open future. Sport Educ Soc 2006; 11 (3): 259-73 6. Munthe C. Selected champions: making winners in the age of genetic technology. In: Tamburrini CT, Ta¨nnsjo¨ T, editor. Values in sport: elitism, nationalism, gender equality and the scientific manufacture of winners. London: Taylor and Francis, 2000: 217-31 7. Munthe C. Ethical aspects of controlling genetic doping. In: Tamburrini C, Ta¨nnsjo¨ T, editors. The genetic technology and sport: ethical questions. London: Routledge, 2005: XII, 223 S 8. Murray TH. Assessing genetic technologies: two ethical issues. Int J Technol Assess Health Care 1994 Fall; 10 (4): 573-82 9. Maron BJ. Distinguishing hypertrophic cardiomyopathy from athlete’s heart: a clinical problem of increasing magnitude and significance. Heart 2005 Nov; 91 (11): 1380-2 10. Corrado D, Thiene G. Protagonist: routine screening of all athletes prior to participation in competitive sports should be mandatory to prevent sudden cardiac death. Heart Rhythm 2007; 4 (4): 520-4 11. Pelliccia A, Fagard R, Bjørnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26 (14): 1422-45 12. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002 Mar 13; 287 (10): 1308-20 13. Maron BJ. Sudden death in young athletes. N Engl J Med 2003 Sep 11; 349 (11): 1064-75 14. Council of Europe. Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Oviedo: The Council of Europe, 1997 15. H.R.493–110th Congress, 2008. Genetic Information Nondiscrimination Act of 2008: an act to prohibit discrimination on the basis of genetic information with respect to health insurance and employment [online]. Available from URL: http://www.govtrack.us/congress/billtext.xpd?bill= h110 [Accessed 2008 Oct 3] 16. Johnson R. The unique ethics of sports medicine. Clin Sports Med 2004; 23 (2): 175-82 17. Dunn WR, George MS, Churchill L, et al. Ethics in sports medicine. Am J Sports Med 2007 May 1; 35 (5): 840-4 18. Waddington I, Malcolm D, Roderick M, et al. Drug use in English professional football. Br J Sports Med 2005 April 1; 39 (4): e18 19. Rankinen T, Bray MS, Hagberg JM, et al. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Med Sci Sports Exerc 2006 Nov; 38 (11): 1863-88 20. Unal M, Ozer Unal D. Gene doping in sports. Sports Med 2004; 34 (6): 357-62
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21. Miah A. Genetically modified athletes: biomedical ethics, gene doping and sport. London: Routledge, 2004 22. Clayton EW. Ethical, legal, and social implications of genomic medicine. N Engl J Med 2003 Aug 7; 349 (6): 562-9 23. Yang N, MacArthur DG, Gulbin JP, et al. ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet 2003 Sep; 73 (3): 627-31 24. Lucia A, Olivan J, Gomez-Gallego F, et al. Citius and longius (faster and longer) with no alpha-actinin-3 in skeletal muscles? Br J Sports Med 2007 Sep; 41 (9): 616-7 25. Roth SM. ACTN3 was never ‘the’ gene for speed. Br J Sports Med 2007 Sep 24 (electronic letter) [online]. Available from URL: http://bjsm.bmj.com/cgi/eletters/41/9/616# 1707 [Accessed 2008 Dec 11] 26. Janssens ACJW, Gwinn M, Bradley LA, et al. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. Am J Hum Genet 2008; 82 (3): 593-9 27. Pigozzi F, Rizzo M. Sudden death in competitive athletes. Clin Sports Med 2008; 27 (1): 153-81 28. Trusty JM, Beinborn DS, Jahangir A. Dysrhythmias and the athlete. AACN Clin Issues 2004 Jul-Sep; 15 (3): 432-48 29. Garratt CJ. Clinical indications for genetic testing in familial sudden cardiac death syndromes: an HRUK position statement. Heart 2008 Apr 1; 94 (4): 502-7
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30. Jordan BD, Relkin NR, Ravdin LD, et al. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 1997 Jul 9; 278 (2): 136-40 31. McCrory P. Boxing and the risk of chronic brain injury. BMJ 2007 Oct 20; 335 (7624): 781-2 32. Shickle D, Chadwick R. The ethics of screening: is ‘screeningitis’ an incurable disease? J Med Ethics 1994 Mar 1; 20 (1): 12-8 33. Gillon R. Ethics needs principles – four can encompass the rest – and respect for autonomy should be ‘first among equals’. J Med Ethics 2003 Oct 1; 29 (5): 307-12 34. Murray T. Genetic exceptonalism and future diaries: is genetic information different from other medical information? In: Rothstein MA, editor. Genetic secrets: protecting privacy and confidentiality in the genetic era. New Haven (CT): Yale University Press, 1997: xvi, 511 35. Yesley MS. Genetic privacy, discrimination, and social policy: challenges and dilemmas. Microb Comp Genomics 1997; 2 (1): 19-35
Correspondence: Prof. Michael John McNamee, Department of Philosophy, History and Law, School of Health Science, Swansea University, Swansea, Wales, UK SA2 8PP. E-mail:
[email protected] Sports Med 2009; 39 (5)
Sports Med 2009; 39 (5): 345-354 0112-1642/09/0005-0345/$49.95/0
LEADING ARTICLE
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Platelet-Rich Therapies in the Treatment of Orthopaedic Sport Injuries Mikel Sa´nchez,1 Eduardo Anitua,2 Gorka Orive,2 In˜igo Mujika3 and Isabel Andia2 1 Unidad de Cirugı´a Artrosco´pica ‘‘Mikel Sa´nchez’’, La Esperanza, Vitoria, Spain 2 Biotechnology Institute IMASD, San Antonio, Vitoria, Spain 3 USP Araba Sport Clinic, Vitoria, Spain
Abstract
Biomedical sciences have made major advances in understanding how tissues repair, and the signalling mechanisms required to achieve this goal are progressively being dissected. Advances in the understanding of tissue repair mechanisms and the pivotal role of growth factors have stimulated the use of platelet-rich therapies by orthopaedic surgeons and sports physicians, mainly with the aim of stimulating and enhancing tissue healing. Autologous activated platelets retained in fibrin matrices are used as a source of molecular signals that control cell fate, including cell growth, cell differentiation and the synthesis of diverse functional proteins. Thus far, platelet-rich technologies have spawned additional ambitious endeavours, including surgical and nonsurgical treatments in sports orthopaedics. Reconstruction of anterior cruciate ligament and tendon surgery and treatment of joint injuries, tendinopathy or muscle tears are but a few examples of the potential applications of this technology in the field of orthopaedic sports medicine. In the present article, some of the most important therapeutic applications using these approaches – especially preparation rich in growth factor (PRGF) technology – are presented, as are some of the limitations, anti-doping concerns and future challenges in the field. In view of a general state of confusion, the concept of platelet-rich plasma needs rigorous definition associated with well characterized products and re-administration procedures. There is evidence that reconstruction of anterior cruciate ligament and tendon surgery combined with PRGF enhances healing and functional recovery; clinical evidence is also appearing in the literature regarding treatment of tendinopathies and osteoarthritis. Currently, the challenge lies in conducting randomized, controlled clinical trials to determine the essential qualities of these technologies. If anti-doping agencies clarify their regulatory guidelines, robust studies in athletes are expected to emerge. Although much research work lies ahead, the current knowledge points to a future in which platelet-rich therapies will continue improving existing conventional approaches to treatment of sports injuries.
The field of sports medicine is currently expanding at a high pace, influencing millions of people from athletes to active individuals who
participate in recreational sport or simply use exercise to stay healthy and active.[1,2] Physical activity and maintenance of good exercise habits are
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promoted by current health systems in the industrialized countries because of the clear link between participating in sport and being fit and healthy. However, while the number of sports practitioners increases, the rate of sports injuries distressing the musculoskeletal tissues is growing and becoming a real problem.[3] For instance, Australia has recently reported 3.7 cases of medically treated sports injuries per 100 persons, with the costs increasing to $A1.5 billion (year of costing 2001) per year.[1] The magnitude of the problem has stimulated significant research efforts focused on injury prevention, identifying ways to minimize risks and to promote protective behaviours.[4,5] Other endeavours target biological questions aiming to provide effective methods for helping the injured athlete/patient to recover within the shortest possible time frame. Those performing basic science believe that understanding the molecular basis of healing mechanisms is at the heart of the development of novel and rational approaches to treat injury. The progressive understanding of mechanisms required for successful tissue repair[6,7] has set the basis for the possibility of making injured tissues heal faster.[8] Among the emerging technologies for enhancing and accelerating tissue healing, a biocompatible and cost-effective approach, broadly referred to as platelet-rich therapy, involves the use of autologous activated platelets retained in fibrin matrices as a source of growth factors released from a three-dimensional scaffold.[9,10] The present paper briefly addresses the main features of these autologous preparations, the most exciting therapeutic applications in sports medicine and the existing current challenges. 1. Tissue Repair and Growth Factors A primary consideration for understanding a therapeutic treatment focused on accelerating healing is to learn from the physiological processes of wound healing and tissue repair. Tissue repair involves a number of complex cellular and molecular events participating through different coordinated phases that are to a great extent shared by the different tissues of the body. Subª 2009 Adis Data Information BV. All rights reserved.
sequent to haemostasis, what primarily emerges is the notion that cells can initiate tissue repair by proliferating, a phase that involves either local cells or undifferentiated cells migrating into the injured area.[11] Concomitantly, physiological angiogenesis (provision of efficient concentration of nutrients and oxygen) takes place, which is critical to guarantee the survival of whole cell number. As proliferation and differentiation phases progress, the predominant cell in the wound site is responsible for producing the new extracellular matrix needed to restore the structure and the functionality of the injured tissue.[12] The challenge in orthopaedic sports medicine is to achieve tissue repair through a new well organized extracellular matrix, which ideally would reach the high mechanical performance and functional levels of the non-injured tissue.[13] It is assumed that the above-mentioned stages of the tissue repair process are mediated and controlled by a wide range of growth factors and cytokines that modulate cell function through direct physical interactions with the extracellular domain of transmembrane receptors.[6] The latter transduce secondary signals, thereby controlling diverse aspects of subcellular biology. Although the roles of all the growth factors involved in tissue regeneration are only partially elucidated, the potential benefits of many of them have been demonstrated. For example, platelet-derived growth factor (PDGF) is a powerful mitogen for connective tissue cells,[14] transforming growth factor-b (TGFb) is not only morphogenic but is also strongly implicated in collagen synthesis,[15] type I insulin-like growth factor (IGF-I) is critical for cell survival, growth and metabolism,[16] and the cooperative actions of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) induce endothelial cell proliferation and migration, thus initiating the angiogenic response.[17] Ultimately, therapeutic approaches to manipulate healing may need to integrate multiple cell types and large signalling networks necessary for the dynamic communication between cells.[18] The need to target various signalling pathways demands the administration of a balanced combination of mediators instead of administering a Sports Med 2009; 39 (5)
Platelet-Rich Therapies in Orthopaedic Sport Injuries
purified isolated growth factor, which could not cope with the multiple requirements of the injured tissue. The delivery of autologous growth factors to the injured tissue may result in significant changes in biological function of the local cells. However, producing biologically, chemically and mechanically normal tissue will require a combination of strategies. So combining the use of platelet-rich products with appropriate mechanical loading regimens might yield better tissue organization in a shorter time and enhanced mechanical properties,[19] which are of paramount importance in sports medicine. 2. Biological Delivery of Growth Factors: Platelet-Rich Therapies The advent of regenerative medicine, aiming to rapidly translate the science into patient care using patients’ own resources, has opened the door to new approaches never imagined before. For example, the use of platelets as vehicles for the delivery of a balanced pool of healing factors has become a new therapeutic treatment since the late 1990s. At that time, platelet-rich plasmas (PRPs) were introduced as autologous modifications of potent adhesives known as fibrin glues.[20,21] The use of platelets as a source of growth factors was particularly fortuitous given that the main initial interest was to take advantage of the adhesive and haemostatic properties of fibrin. Realization of the clinical value of platelet-rich therapies arose from clinical observations such as enhanced bone formation and anti-inflammatory function after oral and maxillofacial applications.[22,23] These anti-inflammatory and antibacterial effects are attributed mainly to the presence of platelets in these preparations.[24,25] Platelets are produced in large numbers from megakaryocytes in the bone marrow. Anucleate platelets circulate for 7–10 days and mediate primary haemostasis. Upon coagulation, platelets secrete a pool of growth factors and other cytokines involved in healing.[26] Since platelets are renowned as the major sources of healing factors within blood clots, the idea that concentrating them at the injured site could somewhat accelerate and optimize the ª 2009 Adis Data Information BV. All rights reserved.
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healing mechanisms set the rationale for the development of PRP. Indeed, platelets carry a-granules and upon activation secrete multiple molecules such as PDGF, TGFb1, platelet factor 4 (PF4), VEGF, endostatins, angiopoietins and thrombospondin-1.[26,27] In addition to providing initial cues for homing of precursor cells to the injury and differentiation, platelets and fibrin are also known to be potent adhesive substrates for cells. As reviewed elsewhere, the outcome of healing is influenced by fibrin structure (thickness of the fibres, number of branch points, the porosity and permeability of the clot) at the wound site.[28] The addition of a platelet-rich preparation at the injury site will accelerate the natural healing process and provide additional support for the binding of not only platelets but also, among others, endothelial cells, smooth muscle cells, fibroblasts, keratinocytes and incoming stem cells. Quite surprising is the recently recognized ability of platelets to reduce pain. The molecular basis of how platelets can influence pain is unknown; one possible explanation is proteaseinduced release of protease-activated receptor-4 peptides from platelets that have anti-nociceptive properties.[29] Not to be forgotten among the advantages in using platelet-rich therapies is the antibactericidal effects of the antibacterial and fungicidal proteins stored in platelets, which may help to prevent infection.[30,31] Most commercial protocols for producing plasma are derived from the same general principle of blood spinning, and the products thereby obtained are denominated by a common terminology, i.e. PRP or platelet concentrates. However, the composition of these products differs widely, both qualitatively and quantitatively. PRP is an excessively general and vague concept, which demands more precise terms. Since a critical difference relies on accompaniment of concentrated leukocyte in the preparation, other authors[32] suggest the term ‘platelet-leukocyte-rich plasma’ (PLRP) for the non-activated product rich in platelets and leukocytes, and platelet-leukocyte gel (PLG) for the same product after its activation. Whether leukocytes have a positive or negative influence cannot be generalized for all tissues and clinical conditions, and remains a Sports Med 2009; 39 (5)
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controversial issue that demands further investigation. A priori, we report several concerns regarding the presence of neutrophils, which contain matrix metalloproteinase (MMP)-8 (referred to as neutrophil collagenase, once thought to be expressed exclusively in neutrophils and polymorphonuclear leukocytes) and also express MMP-9.[33] The release of reactive oxygen species by neutrophils may also be relevant. In fact, the paradigm suggests that neutrophils infiltrate injured tissue and in the process of assisting removal of disrupted tissue, exacerbate or increase the original damage.[34,35] In addition, there are in vitro data demonstrating that neutrophils can injure skeletal myotubes.[36] The available evidence, therefore, suggests that infiltrating neutrophils in injured skeletal muscle can act as a cytotoxic agent causing secondary destruction to muscle.[37] Additionally, the characteristics of the product and the re-administration procedures to patients/ athletes may also differ widely, raising controversial opinions regarding their therapeutic value.[38] In view of the general state of confusion, it is necessary to use a precisely defined terminology associated with well characterized products[39] while justifying the application procedures. The preparation rich in growth factor (PRGF) is an alternative technology developed by our group to formulate and use platelets as growth factor and protein reservoir units. The term ‘PRGF’ identifies 100% autologous and biocompatible products elaborated using a one-step centrifugation process, and sodium citrate and calcium chloride as anticoagulant and activator, respectively.[9] The latter is critical to achieve a sustained release of growth factors; moreover, using a standardized dose of calcium chloride, while avoiding the addition of exogenous thrombin, grants control over the liquid-gel (fibrin matrix) transformation and confers versatility on administration procedures.[40] For example, one possibility is to inject the activated liquid, a process that will result in local fibrin matrix development and proteins being readily extruded from the matrix in situ. Alternatively, the fibrin scaffold can be formed ex vivo and then implanted in the chosen site prior to retraction. Furthermore, if the fibrin matrix is incubated ex vivo for 40 minutes or so, the fibrin ª 2009 Adis Data Information BV. All rights reserved.
structure is modified in such a way that it retracts and turns into an elastic dense membrane. The latter can be used to enhance cicatrization of soft tissues.[41] As shown in figure 1, the preferred administration procedure depends on the specific management of each medical condition. Being aware of possible undesired effects provoked by proinflammatory proteases and acid hydrolases released from leukocytes, we exclude them from PRGF preparations. Neutrophils could be particularly detrimental for the injured tissue,[9] especially in muscle strains[36] or joint infiltrations, as discussed above.[33] Ultimately, the biosafety and versatility of this approach has inspired and stimulated its therapeutic use in a wide range of medical and scientific fields,[42,43] and to an outstanding degree in orthopaedics and sports medicine. 3. Platelet-Rich Therapies in Orthopaedic Sports Medicine The emergence of PRPs as a cutting edge technology in the treatment of sports injuries appears intriguing. The easy preparation protocols and the biosafety and versatility of the platelet-based preparations and their reduced cost have stimulated the interest of sports physicians and orthopaedic surgeons. The following examples represent some of the most interesting current approaches in the treatment of acute and chronic sports injuries. 3.1 Tendons
One interesting focus of research with plateletrich therapies is tendon repair. Tendons consume comparatively low energy by themselves, resulting in a low metabolic rate that entails slow healing after injury. However, it has been shown that several growth factors can stimulate tendon repair after exogenous local application.[44] Considering that the pool of plasma and plateletsecreted factors may potentially benefit tendon repair, we have undertaken in vitro studies on tenocytes, the dominant cell type in tendons and also responsible for tendon physiological or Sports Med 2009; 39 (5)
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a
b
c
d
Fig. 1. Relevant procedures for growth factor and protein delivery in orthopaedic sports injuries: (a) the liquid-activated preparation rich in growth factor (PRGF) can be infiltrated within the capsular joint in patients with osteoarthritis; (b) PRGF fibrin scaffold is implanted in a cartilage defect by arthroscopy; (c) PRGF is injected in the injured tendon tissue to restore the biological environment; (d) the surgically treated patellar tendon is covered with dense fibrin membranes to enhance soft tissue healing.
pathological response to changes in the biological and mechanical environment. We have observed that the pool of growth factors released from an autologous PRGF increased the proliferation of human tendon cells significantly and stimulated them to produce growth factors such as VEGF and HGF.[45] The cooperative paracrine action of these growth factors will promote angiogenesis that is directly related to tendon healing capability and tendon graft integration. Additionally, since HGF is a potent antifibrotic agent, its secretion may help to reduce the scar formation around tendon tissues.[46] Further research in a sheep model showed that repetitive injection of PRGF within Achilles tendon fascicles triggered a healª 2009 Adis Data Information BV. All rights reserved.
ing response assessed by increased cell number and angiogenesis, and did not provoke fibrosis.[47,48] Other researchers have reported that injections of PRP 1 week postoperatively increased tendon regeneration and strength.[49] Recently, it has been observed that locally injected PRP is useful as an activator of circulation-derived cells for enhancement of the initial tendon healing process.[11] This basic information gave us insight into how PRGF may benefit tendon healing when applied clinically. In operative treatment for serious structural damage such as partial or complete tendon tears, healing can be enhanced by PRGF application during the surgical procedure. Sports Med 2009; 39 (5)
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Using this ground-breaking surgical approach in athletes, we observed a significant acceleration in functional recovery after surgical repair of ruptured Achilles tendon compared with a matched group who had conventional surgery.[50] In addition, we found that the early stimulatory effect induced by PRGF can also have long-term consequences (after >18 months) such as decreased cross-sectional area in Achilles tendons treated with PRGF compared with conventional surgery. Typically, tendon injuries are traumatic and acute but in many cases they become chronic. One typical problem in orthopaedic sports medicine is tendinopathy. It is considered as a syndrome characterized by tendon pain, localized tenderness and swelling that impair performance. It is often assumed that the latter is one of the most exasperating problems for patients and physicians in orthopaedic sport medicine. Being related to repetitive movements and overuse, the location of such injuries is sport specific. Patellar tendinopathies, for instance, are often associated with jumping sports such as basketball, volleyball and high jump,[51] while tennis players and golfers are more prone to medial and lateral epicondylitis.[52] The use of PRP in this context might be focused on restoring the normal tissue composition while avoiding further degeneration. In these conditions, ultrasound-guided PRP injection may offer an alternative treatment over palliative or operative treatments. Such treatment was evaluated in a cohort study by Mishra et al.,[53] reporting a reduction of pain in PRP treatment of chronic severe elbow tendinosis. Curiously, others have reported that autologous blood injection under ultrasound guidance appears to be an effective treatment of severe medial epicondylitis, commonly known as golfer’s elbow, as shown by pain reduction and an index of elbow performance.[54] 3.2 Joint Injuries
People who participate in sports have an increased risk of joint damage. High levels of impact and torsional loading disrupt articulations, provoking a wide array of joint disorders. For instance, ª 2009 Adis Data Information BV. All rights reserved.
anterior cruciate ligament (ACL) injuries are usually traumatic and sports related,[55,56] with approximately 100 000 ACL reconstructions performed in the US each year[57] at a cost just under $US1 billion (year of costing 1998) per year.[58] Reconstruction is the surgical treatment of choice, as direct primary repair has been shown to result in persistent laxity and instability of the knee. In view of the clinical relevance of the problem, several groups have attempted to fabricate tissueengineered ligaments using natural biomaterials and a wide range of nanometre-sized artificial scaffolds.[59] Deriving knowledge from preclinical research and clinical activities in a synergistic fashion showed the ways to assist ACL reconstructive surgery introducing PRGF technology. In this context, PRGF may bridge the gap between inactive scaffolds and cell biology, offering to the scaffold structure the biological stimulation necessary to become transformed into a functional remodelling tissue.[60] This novel approach to creating fully integrated bioactive grafts was proposed by our group 6 years ago,[61] using the traditional paradigm of in vivo tissue engineering in which platelet-rich fibrin was infiltrated to transfer growth factors to autologous or homologous grafts, therein providing biological cues for cell migration, proliferation, angiogenesis and remodelling. The increased bioavailability of angiogenic factors released from PRGF will promote a rapid blood supply to the graft, contributing to a rapid remodelling.[45] Aiming to achieve successful fixation of the graft and prompt functional efficacy, PRGF is also applied within both femoral and tibial bone tunnels created by the surgeons to secure the ends of the graft. Moreover, to provide early strength and optimal healing we used biological anchors created by mixing PRGF with the autologous bone plugs obtained during the procedure. Using this approach it is possible to enhance the long-term anchoring of the graft to the bone. In another approach we observed exciting results after intra-articular administration of PRGF in the arthroscopic treatment of an avulsion of articular cartilage in the knee of a young soccer player.[62] Full-thickness cartilage defects treated with PRGF showed enhanced mechanical Sports Med 2009; 39 (5)
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properties in a rabbit model.[63] Other groups[64,65] have reported the ability of PRP to support chondrogenesis and the healing of meniscal defects by implanting PRP combined with cultured cells in animal models. These results are stimulating, since both the avascular cartilage and meniscus have limited or no chances for proper functional repair. Damage to the knee in an early stage of life can lead to osteoarthritis in a later stage, which is called post-traumatic or secondary osteoarthritis. The latter is a common medical problem for athletes with a history of joint injury. It has been reported that >80% of American football players with a previous knee injury had evidence of osteoarthritis 10–30 years after retiring from competition.[66] Competitive soccer players present with an increased prevalence of osteoarthritis in the lower extremity joints compared with agematched controls.[67] Premature osteoarthritis is also a serious concern in the growing community of ‘baby boomers’ and recreational athletes who are too young for knee replacements. Plateletrich therapies may be promising in these populations. Basic research performed in our laboratory showed that intra-articular PRGF might be beneficial in restoring hyaluronic acid concentration within the joint and switching angiogenesis to a more balanced status, although it does not halt the effects of interleukin-1b on synovial cells.[68] Correspondingly, our preliminary clinical results showed that intra-articular injection of PRGF may be a new therapeutic option for osteoarthritis treatment in selected patients.[69,70] However, this outstanding development is still in its infancy and continued research is needed to ascertain the potential value and the underlying biological effects. Accordingly, we have launched a randomized, multicentre clinical trial to evaluate the therapeutic effect of PRGF infiltrations within the osteoarthritic knee.[71] 3.3 Muscle Tears
A muscle strain typically keeps athletes out of action for several weeks, and sports clubs employ fulltime medical staff in order to minimize this down-time. Conventionally, treatment comprises ª 2009 Adis Data Information BV. All rights reserved.
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physiotherapy, which uses physical modalities such as ice, electrotherapy, massage, mobilization, manipulation and exercise to optimize the healing process. In these cases, platelet-rich therapies are applied as an alternative to conventional approaches, because of the promise of accelerating muscle healing and reducing a player’s injury time. In this approach the early blood clot is substituted with platelet-rich fibrin, which maintains the regenerative space, provides supraphysiological concentrations of healing factors, and acts as the primer of the overtaking healing phases. In this context, special attention should be given to the composition of PRP products. As discussed in section 2, when preparing PRGF we avoid the presence of leukocytes, since neutrophils can exacerbate or increase the original muscle damage.[34,35] In one study, after ultrasound guided injections of PRGF in 22 muscle injuries of 20 high-level professional athletes, full recovery of functional capabilities was restored in as early as half of the expected recovery time. Furthermore, fibrosis did not appear in any of the treated cases and no re-injuries occurred in any athlete after resuming their normal sports activities.[72] 4. Future Directions Platelet-rich therapies represent a new biomedical technology for the stimulation and acceleration of healing and tissue regeneration. The above examples represent only some of the interesting current approaches, but the authors believe this technology may see new exciting developments in the next few decades. One important consideration for future expansion of the field is to clarify any possible concern related to the biosafety of this approach, and especially any anti-doping concern. The recent World Anti-Doping Agency code, which prohibits all use of growth factor therapies in elite sport, has provoked distress among sports medicine practitioners. A detailed analysis of the prohibited S2 section reveals that only IGF-I may have a possible connection with the platelet-rich therapies described in the article.[73] However, there are at least two compelling reasons that eliminate Sports Med 2009; 39 (5)
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any anti-doping concern from the therapeutic use of PRGF. Firstly, the doses of IGF-I released from the PRGF are sub-therapeutic,[46] in terms of inducing systemic anabolic actions, by a factor of between 500 and 1000 (100 ng vs 160 mg). Secondly, the availability of most IGF-I is modulated by a binding protein[74] (IGFBP3) and only 1% of the total IGF-I released from the PRGF is unbound, and therefore biologically available and active, ready to bind to receptors IGF-IRs inducing biological outcomes. Additionally, the short half-life (10 minutes) of this unbound and active IGF-I makes an alteration in systemic levels unlikely. In any case, such a controversy may also affect other accepted therapeutic approaches, including the use of autologous tissue such as tendon grafts in the ACL reconstructions or bone grafts, as both applications imply the release of IGF-I.[75,76] Therefore, the authors believe that it is necessary for regulatory and anti-doping agencies to refine and clarify their regulatory guidelines and prohibited lists in order to avoid confusion and to raise awareness of the current clinical utility of these types of products in general and especially of PRGF. 5. Conclusions In summary, recent advances in the understanding of the pivotal role of growth factors in tissue repair mechanisms have opened new perspectives for the use of platelet-rich therapies to enhance tissue healing after orthopaedic sports injuries. PRPs applied at the injury site accelerate the physiological healing process, provide support for cellular binding, reduce pain and have anti-inflammatory and antibacterial effects. Proper characterization of available products and application procedures is needed before these therapies can be widely applied in the context of sports medicine. One of the most thoroughly analysed and researched of such products is PRGF, which has shown therapeutic value in tendon repair and treatment of joint injuries, and promising results are available in the treatment of osteoarthritis and muscle tears. Although much research work lies ahead, the current knowledge points to a future ª 2009 Adis Data Information BV. All rights reserved.
in which platelet-rich therapies will continue improving existing conventional approaches to patient care. Acknowledgements The research of this group is partially funded by the Basque and Spanish Governments. Eduardo Anitua, Gorka Orive and Isabel Andia work in the Research Department of the Biotechnology Institute, a dental implant company that markets a system for preparing PRP for therapeutic use.
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Correspondence: Dr Isabel Andia, c/o Leonardo Da Vinci 14, 01510 Minano, Alava, Spain. E-mail:
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REVIEW ARTICLE
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Characteristics of Physical Activity Guidelines and their Effect on Adherence A Review of Randomized Trials Ryan E. Rhodes,1 Darren E.R. Warburton2 and Holly Murray1 1 Behavioural Medicine Laboratory, Faculty of Education, University of Victoria, Victoria, British Columbia, Canada 2 Cardiovascular Physiology and Rehabilitation Laboratory, Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Data Sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Operational Definitions of Dependent and Independent Variables . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Inclusion and Exclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Data Extraction and Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1 Manipulations of Total Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Manipulations of Accumulation of Activity per Day . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1 Aerobic Activities Compared with Resistance Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2 Exercise Compared with Lifestyle Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3 Walking Compared with Running . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Interactions among Prescription Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1 Total Volume of Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2 Energy Expenditure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Prescription characteristics and guidelines of recommended physical activity have been suggested as factors that may affect behavioural adherence; however, no review has critically appraised the current evidence. Thus, the purpose of this article was to review the effect of frequency, intensity, duration and mode on physical activity adherence and provide meta-analytical summaries of the findings. A total of 27 peer-reviewed studies met inclusion criteria and random-effects meta-analytical procedures, correcting for sampling bias, were employed where possible. Overall, results showed that the
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effect of physical activity guideline characteristics on behavioural adherence is not particularly robust as evidenced by a lack of unified findings and almost no evidence for the interaction among these factors (e.g. volume of activity and energy expenditure). Frequency (d = 0.08), intensity (d = 0.02), duration (d = 0.05) and mode of activity (ds = 0.03–0.10) showed generally null/trivial effects. Factors unrelated to the recommended guidelines may be of greater importance when considering behavioural adherence issues. Social cognitive, personality, and environmental or socioeconomic factors have amassed considerable evidence as correlates or determinants of physical activity, and health promoters may wish to consider these variables before basic physical activity characteristics.
Evidence on the physical and mental health benefits of regular physical activity continues to accrue.[1-4] Routine physical activity is thought to aid over 25 chronic conditions.[5,6] Despite general public awareness of the health benefits of physical activity,[7,8] less than half of the population in North America meet recommended international guidelines.[7,9] Thus, there is a continued need to understand the factors that may facilitate or impede the regular physical activity adherence of adults. The prescription characteristics and guidelines of recommended physical activity itself has been suggested as one such factor.[4] At present, a variety of international physical activity guidelines and/or consensus statements have been developed (see Blair and Brodney[1] for a recent review). The history of these guidelines has generally followed an initial focus on vigorousintensity aerobic activity at set frequencies (i.e. three to five times per week) and durations (i.e. 30–60 minutes)[10] to a current focus on moderate- or vigorous-intensity lifestyle activity (with aerobic focus) at similar frequencies, but with the possibility of accumulating duration in 10-minute bouts.[11-13] Health Canada, in conjunction with the Canadian Society for Exercise Physiology, has even included recommendations for daily light-intensity activity (including light walking and gardening) for 60 minutes or more.[12] These recommendations generally reflect increasing evidence suggesting a minimal level of physical activity required to obtain health benefits.[2,4] However, these guidelines also acknowledge that a dose-response relationª 2009 Adis Data Information BV. All rights reserved.
ship exists such that further improvements in health status can be obtained with greater intensities and/or volumes of physical activity.[5] Thus, the general downward shift of physical activity guidelines has been predicated largely on assumptions of behavioural adherence.[2,4] Specifically, it has been assumed that lower intensity activity in short bouts will be more palatable to sedentary individuals and thus result in superior adoption and subsequent continuance with the behaviour.[5] The evidence for this assumption at the time these initial decisions were made (i.e. mid1990s) was scant, as pointed out in reviews.[14,15] Although the assumption is logical, prior unsystematic narrative reviews suggested that exercise prescription characteristics were either not important to adherence[15] or insufficient information was available to make a judgement.[14] The most convincing evidence came from passive longitudinal survey research, where exercise adoption and continuance rates were higher for those who engaged in moderate-intensity activities compared with vigorous-intensity activities.[16] Some additional evidence was presented as a collection of small training studies by Pollock[17] showing that high intensity and longer duration, but not frequency of exercise prescribed, affected adherence negatively. Finally, in concert with the timing of the physical activity recommendations coming from the US Surgeon General’s report,[3] a meta-analytical review of interventions by Dishman and Buckworth[18] showed that prescription characteristics may be important considerations for behaviour change. This review highlighted that physical activity Sports Med 2009; 39 (5)
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mode (active leisure superior to structured exercise) and intensity (moderate superior to vigorous) showed greater adherence effects when weighted by sample size. As an important note, however, these same effects were not observed when the unweighted effects or when multivariate analyses1 of other potential intervention moderators were considered. These results therefore suggested mixed or tentative findings. Given that behavioural considerations have helped shape the current guidelines for recommended physical activity, it seems prudent to gather and appraise critically the current evidence for the effect of prescription characteristics on adherence. The prior meta-analysis[18] focused on the topic has become dated by 12 years and past consensus statements or narrative reviews have not focused on actual experimental designs where prescription characteristics have been manipulated. Thus, the purpose of this article is to determine the impact that various physical activity prescription components have had on physical activity adherence (i.e. behavioural participation in physical activity) and provide meta-analytical summaries of the findings. 1. Method 1.1 Data Sources
This review was obtained through systematic database searches, and manual cross-referencing of bibliographies. The databases used included PubMed, Web of Science, PsycINFO and SportDiscus, representing databases from multiple disciplines related to health and physical activity. Search terms included various combinations of the keywords ‘frequency’, ‘intensity’, ‘duration’, ‘type’, ‘mode’, ‘adherence’ and ‘physical activity’. 1.2 Operational Definitions of Dependent and Independent Variables
Adherence was defined as participant compliance with the prescribed physical activity
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guideline, but behavioural participation (i.e. percent attendance/participation in prescribed guidelines) was considered the gold standard measure when available.[7,9] Physical activity frequency was defined in terms of days per week, and intensity was defined in terms of light (20–39% heart rate reserve [HRR], 50–63% maximum heart rate [HRmax]), moderate (40–59% HRR, 64–76% HRmax) and vigorous (60–84% HRR, 77–93% HRmax).[2] Duration was defined in terms of minutes and mode was defined by different types of activity.[7,9] Finally, total volume of physical activity (i.e. frequency · duration per week at fixed intensities) and energy expenditure (kJ/week) were also included. Energy expenditure was estimated based on the information provided in each study and converted to kilojoules using established criteria.[20] 1.3 Inclusion and Exclusion Criteria
Studies included in this review were randomized trials from English peer-reviewed scholarly journals, published up to November 2007 (date of submission). Dissertations, theses and conference proceedings were not included in this review. The inclusion criteria extended to all studies of adults aged 18 years or older, including one or more of frequency, intensity, time (duration) or mode of activity as the independent variables and a measure of behavioural adherence as one of the dependent variables. Those studies measuring retention only, and not adherence, were excluded. 1.4 Analysis Methods
Based on a priori classification of physical activity guideline and prescription characteristics,[21] results were grouped and appraised by frequency, intensity, duration, mode, total volume of activity and energy expenditure. Attempts to best match/isolate physical activity characteristics were made when multi-arm trials were present with multiple groups of different characteristics
1 Dishman and Buckworth[18] did note a statistically significant b for intensity (b = 0.09; p < 0.02) in multivariate analyses, but the effect size is within the range of trivial considering Cohen’s suggested values.[19] We have, therefore, considered the effect as null in our narrative assessment.
ª 2009 Adis Data Information BV. All rights reserved.
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(e.g. moderate-intensity high-duration was compared with vigorous-intensity high-duration for comparisons of intensity even when a vigorousintensity low-duration condition was also present). Vote-counting procedures based on significant/null findings were performed as well as narrative appraisal of the findings by study quality.[22] Effect sizes in the form of Cohen’s d or h were also calculated when the necessary statistical information was available. Cohen[19] outlines h = 0.68) was from a decline in adherence due to injury from groups who performed vigorous activities with >10 500 kJ/week. Thus, meeting guidelines with weekly energy expenditure between 4000 and 8500 kJ/week appears to be null on adherence, but higher energy expenditures may yield lower adherence. This is consistent with Sports Med 2009; 39 (5)
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most international physical activity guidelines that advocate the adoption of moderate-intensity physical activity with a minimal weekly energy expenditure of approximately 4200 kJ (1000 kcal).[5] 3. Discussion This was the first focused review of physical activity guideline and prescription characteristics and their effect on behavioural adherence. Prior commentary on this topic focused on unsystematic narrative reviews or has become dated by 12 years or more. Given the role that behavioural considerations have played and continue to play in the creation of international physical activity guidelines,[5] the critical and systematic appraisal of this collected literature is timely. Overall, 27 studies were identified as meeting our inclusion criteria but only a small number of studies focused on each specific physical activity characteristic. The paucity of research notwithstanding, the quality of research on these topics has been excellent. With few exceptions, studies focused on target populations of sedentary adults (i.e. those who are the intended audience of physical activity guideline messaging[5]), employed multiple measures of behavioural adherence, used longitudinal designs up to 2 years, included robust sample sizes, and manipulated the physical activity characteristics under study within sensible/plausible ranges based on current practice or existing evidence. Most research has not controlled or isolated each possible physical activity characteristic so that independent contributions of variables can be evaluated. This is understandable given the dynamic nature of frequency, intensity, duration and mode, and an overriding interest to control for energy expenditure across various manipulations. Experimental trials, such as these studies reviewed, also have the potential of sampling limitations that could affect the generalizability of results. That is, sedentary people who volunteer for research trials may be somewhat different in terms of motivational characteristics, reach and opportunity from the broader population in which the study hopes to generalize to. Furthermore, this limited literature has generally neglected to use ª 2009 Adis Data Information BV. All rights reserved.
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intent-to-treat analyses (only 40% of studies). This may bias the sample generalizability further because less motivated individuals may drop out across a trial. Still, our review of findings allows for some conclusions to be drawn and recommendations for future research. Considerations of frequency have generally shown null results in terms of their impact on adherence. However, there is some variability around the comments from participants across studies, and thus consideration of recommending high frequency activities and their potential negative impact on physical activity may be necessary. King et al.,[44] for example, reported that anecdotal commentary from participants suggested that the difference in programme adherence at 24 months was due to frequency issues. Specifically, the high frequency (five sessions per week) condition indicated that it was more difficult to adhere to the original prescription due to the additional time demands. Despite this anecdotal commentary, however, the effect of frequency on adherence is not robust and we suggest it should not receive considerable attention during the development of guidelines. In an early review on characteristics of physical activity as determinants of adherence, Dishman[14] tentatively concluded that higherintensity activities may negatively influence behaviour. Thirteen years later, our review now provides a slightly stronger conclusion. There is limited evidence that higher recommended intensities affect behavioural adherence when compared with moderate-intensity or even lightintensity activity, and disentangling these findings through careful scrutiny of the research strengthens the null hypothesis. Thus, we conclude that the recommended intensity of physical activity is not a robust determinant of adherence, but further studies isolating intensity independent of other characteristics may still be warranted. In future research, specific consideration of the ventilatory threshold may improve the groupings of light, moderate and vigorous intensity conditions. Shephard[53] has highlighted that absolutelevel ranges of intensity may be of limited value when applied to sedentary middle-aged and older Sports Med 2009; 39 (5)
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populations because of such variability in actual work among these populations. Furthermore, research on single bouts of physical activity have supported the importance of ventilatory threshold to perceived exertion and positive affect.[54-56] That is, as exercise reaches and exceeds ventilatory threshold, the activity is perceived as less enjoyable and of far greater exertion; this, in turn, may have an effect on adherence because affective expectations are a strong predictor of physical activity participation.[57-59] Although most existing studies also used some form of relative intensity assessment (e.g. perceived exertion), some research may be partially obscuring the intensity gradient, which could explain the null findings and warrants further research. Intensity of physical activity is clearly an important factor in terms of understanding the quality of the workload and the impact on both fitness and health.[2] It seems prudent, therefore, to continue research on intensity and physical activity adherence to determine whether behavioural considerations should be given any credence during the creation of recommended intensity guidelines. In terms of studies that have compared different durations of recommended physical activity, the literature is relatively united in showing that either single 30-minute bouts or accumulation of activity in 10-minute bouts does not affect adherence. Interestingly, the initial advocacy for this approach to achieving physical activity was based on behavioural considerations.[4] Preliminary evidence is now suggestive that short bouts of activity accumulated across the day may be sufficient to accrue health benefits;[5] however, the behavioural considerations need not take primary consideration in this recommendation. Manipulation of single-bout durations is also null at present, but there is simply a lack of controlled studies on the matter. Additional well controlled research would be helpful to reach a definitive conclusion. Similar to the other physical activity prescription characteristics, studies that have evaluated different modes of activities generally show null results. These studies have focused on common and practical differentiations (i.e. jogging vs ª 2009 Adis Data Information BV. All rights reserved.
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walking, lifestyle vs structured exercise, aerobic vs strength) and thus the null results are both interesting and provide helpful information when creating and suggesting exemplars of physical activity that people may wish to perform. From an applied perspective, the results of this review provide evidence that practitioners (when designing a physical activity programme for a client) do not need to give strong consideration to any effect that guideline factors may have on adherence. Thus, an exercise prescription can be based primarily around the health-related fitness and safety goals of the client. This is particularly important when dealing with clinical populations. Recent research has actually shown that high-intensity, interval-type exercise training may lead to greater health benefits for various clinical populations (including patients with cardiovascular disease).[23] However, many practitioners have been concerned with using highintensity exercise because of the potential for reduced exercise adherence. These review findings suggest evidence contrary to previously held axioms that high-intensity exercise would lead to reduced exercise adherence. This information is particularly important for practitioners (such as Canadian Society for Exercise PhysiologyCertified Exercise Physiologists and the American College of Sports Medicine-Exercise Specialists) who design physical activity programmes for varied healthy and clinical populations. Some additional limitations to the current literature suggest avenues for sustained research. First, the extant literature has focused primarily on middle-aged adults. Although clearly an important population in which to focus these types of studies, young adults and older adults may be worthy of focused evaluation. Young adulthood represents the most dramatic shift to inactivity across the population[60-62] and characteristics of physical activity recommendations during that time may be prudent. For example, young adults are typically burdened and fatigued by career and early parenthood responsibilities;[63,64] it may be that factors such as duration (10 minutes vs sustained) and intensity (moderate vs vigorous) are more strident at this age. For older adults, far greater variability in fitness is present than Sports Med 2009; 39 (5)
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in other populations[65] and this difference may be of greater importance to physical activity recommendations.[53,66] Similar to age, an evaluation of sex differences and recommended physical activity characteristics may prove helpful. Most studies with mixed sex samples did not report on differences and our analysis across this literature did not reveal marked differences by sex; however, some evidence was present to suggest that women may adhere better to moderate-intensity activity, while men may adhere better to vigorous-intensity activity.[41,32] The topic may warrant specific and focused comparisons. Finally, the current physical activity recommendations in terms of frequency, intensity and duration offer a wide range of alternatives for the population.[11,12] This is a positive because it offers great freedom of choice in which health promoters can then tailor to meet their client’s desired needs without extended consideration of how these characteristics may affect adherence. A potential drawback of this approach, however, is that the messaging of these guidelines may be viewed as convoluted and difficult to interpret. An extension to this literature may therefore benefit from evaluating health literacy and its impact on physical activity adoption and adherence based on different guidelines.[67] 4. Conclusions The effect of physical activity guideline characteristics on behavioural adherence is not particularly robust as evidenced by a lack of unified findings and almost no evidence for the interaction of these factors (e.g. volume of activity, energy expenditure). Frequency, intensity, duration and mode of activity showed generally null effects. Factors unrelated to the recommended guidelines may be of greater importance when considering behavioural adherence issues. Social cognitive, personality and environmental or socioeconomic factors have amassed considerable evidence as correlates or determinants of physical activity and health promoters may wish to consider these variables before basic physical activity characteristics. ª 2009 Adis Data Information BV. All rights reserved.
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Acknowledgements Ryan E. Rhodes and Darren E.R. Warburton are supported by Scholar awards from the Michael Smith Foundation for Health Research and New Investigator awards from the Canadian Institutes of Health Research. Dr Rhodes is also supported by funds from the Canadian Diabetes Association, Social Sciences and Humanities Research Council of Canada and the Human Early Learning Partnership (British Columbia Ministry of Family). The authors report no conflict of interest for this paper.
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61. Caspersen C, Pereira MA, Curran KM. Changes in physical activity patterns in the United States, by sex and crosssectional age. Med Sci Sports Exerc 2000; 32: 1601-9 62. Statistics Canada. Canadian community health survey 1994–2003. Ottawa (ON): Statistics Canada, 2005 63. Bellows-Riecken KH, Rhodes RE. The birth of inactivity? A review of physical activity and parenthood. Prev Med 2008; 46: 99-110 64. Rhodes RE, Symons Downs D, Bellows Riecken KH. Delivering inactivity: a review of physical activity and the transition to motherhood. In: Allerton LT, Rutherfode GP, editors. Exercise and women’s health: new research. Hauppauge (NY): Earthlink Science Press, 2008: 105-27 65. Paterson DH, Cunningham DA, Koval JJ, et al. Aerobic fitness in a population of independently living men and women aged 55-86 years. Med Sci Sports Exerc 1999; 31: 1813-20 66. Fitzsimons CF, Greig CA, Saunders DH, et al. Responses to walking-speed instructions: implications for health promotion for older adults. J Aging Phys Act 2005; 13: 172-83 67. Wolf MS, Gazmararian JA, Baker DW. Health literacy and health risk behaviors among older adults. Am J Prev Med 2007; 32: 19-24
Correspondence: Dr Ryan E. Rhodes, Behavioural Medicine Laboratory, Faculty of Education, University of Victoria, PO Box 3015 STN CSC, Victoria, BC, V8W 3P1, Canada. E-mail:
[email protected] Sports Med 2009; 39 (5)
Sports Med 2009; 39 (5): 377-387 0112-1642/09/0005-0377/$49.95/0
REVIEW ARTICLE
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Swimming Exercise Impact of Aquatic Exercise on Cardiovascular Health Hirofumi Tanaka Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas, USA
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Benefits and Popularity of Swimming. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Lack of Swimming Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Swimming and Coronary Heart Disease Risk Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Maximal Aerobic Capacity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Arterial Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Blood Lipids and Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Carbohydrate Metabolism and Insulin Sensitivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Bodyweight and Body Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Swimming and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
377 378 379 379 379 380 381 382 383 384 384
Swimming is an exercise modality that is highly suitable for health promotion and disease prevention, and is one of the most popular, most practiced and most recommended forms of physical activity. Yet little information is available concerning the influence of regular swimming on coronary heart disease (CHD). Exercise recommendations involving swimming have been generated primarily from unjustified extrapolation of the data from other modes of exercise (e.g. walking and cycling). Available evidence indicates that, similarly to other physically active adults, the CHD risk profile is more favourable in swimmers than in sedentary counterparts and that swim training results in the lowering of some CHD risk factors. However, the beneficial impact of regular swimming may be smaller than land-based exercises. In some cases, regular swimming does not appear to confer beneficial effects on some CHD risk factors. Moreover, swimming has not been associated with the reduced risks of developing CHD. Thus, extrapolation of research findings using land-based exercises into swimming cannot be justified, based on the available research. Clearly, more research is required to properly assess the effects of regular swimming on CHD risks in humans.
A number of epidemiological studies have demonstrated the benefits of regular physical activity for the prevention of cardiovascular disease.[1-3] In order to facilitate the implementation
of proper exercise programmes, a variety of national and international health and exercise organizations have published a number of exercise guidelines.[3-7] According to these guidelines,
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any activity that uses large muscle groups, can be maintained continuously, and is rhythmical and aerobic in nature is recommended as the modality of physical activity. Swimming fits perfectly with the recommended exercise modality description. Indeed, swimming is always included as a form of regular aerobic exercise that is recommended for health promotion as well as prevention and treatment of risk factors for cardiovascular disease in men and women.[4-8] However, there is little scientific evidence to date indicating that swimming is equally efficacious to land-based exercise modes (e.g. walking and cycling) in reducing cardiovascular risks. Regular swimming has been widely promoted and prescribed without the underpinning of firm scientific support from clinical studies. These recommendations have been generated primarily from unjustified extrapolation of the data from other modes of exercise. This is unfortunate, because the public expects that the authoritative advice from medical and scientific bodies is supported and justified by scientific studies. In this review, using the limited research studies conducted in swimming or swimmers, we address general questions such as whether swimmers who train just as hard, as long and as frequently as other athletes in land-based exercise modes demonstrate the same favourable risk profiles for coronary heart disease (CHD), and whether swimming training interventions reduce risk factors for CHD. It should be noted that swimming is a popular mode of physical activity to determine the effects of exercise in rodents, and a number of research studies have been conducted using rodents.[9-11] However, swimming in rodents may not be directly applicable to humans, because swimming rats spend more than 50% of the time being submerged and exhibit signs of hypoxia, hypercapnia, acidosis and an exaggerated diving reflex.[12] For this reason, the primary focus is placed on human studies, and only a few animal studies are included in this review. Additionally, because human studies focusing on swimming and cardiovascular health are very limited, studies using a wide variety of participants of different ages, ª 2009 Adis Data Information BV. All rights reserved.
Tanaka
sex and health states are compiled and presented together in this review. 1. Benefits and Popularity of Swimming Swimming is an attractive form of exercise, as it is easily accessible, inexpensive and isotonic. Because it does not involve bearing of bodyweight, due to the buoyancy of water, compressive joint forces are lower and, as a consequence, adverse impact on the musculoskeletal system as well as injuries are rare.[13,14] Indeed, the incidence of orthopaedic injury among swimmers is substantially lower than in runners or cyclists.[14] Moreover, because of colder temperature as well as increased thermoconductivity of water, the incidence of heat-related illness is small.[15] As such, it is an ideal form of exercise for obese patients, the elderly and patients with arthritis. However, surprisingly little is known about the effects of regular swimming for health promotion and disease prevention. In contrast to the public perception that swimming is a ‘minor’ form of exercise, it is one of the most popular and most practiced forms of physical activity.[16-21] In the US and most industrialized countries, swimming is the second most popular dynamic exercise modality, second only to walking.[16-21] According to the US census, approximately 20% of the US population performed swimming in a year, whereas about 33% did walking.[21] Among overweight and pregnant women, swimming is the most preferred type of physical activity.[22] Swimming is particularly popular in the Southern states, where the climate is more suitable for swimming. As one of the moderate-sized metropolitan cities in the South of the US, the city of Austin, Texas, has 27 neighbourhood pools, 12 wading pools and six municipal pools. Additionally, many residents have swimming pools at their homes. Indeed, an estimated 8.6 million swimming pools are in public or residential use in the US.[23] Use of swimming as an exercise therapy will have enormous public health implications as more older adults, who exhibit elevated risks of developing CHD, migrate to warmer climates, where the prevalence of obesity is highest. Sports Med 2009; 39 (5)
Swimming Exercise and Cardiovascular Risk Factors
2. Lack of Swimming Research In spite of the widespread popularity of swimming,[16-21] research focusing on swimming and cardiovascular disease is heavily underpursued. The relative lack of swimming research can be attributed to a number of factors. Firstly, it is difficult to make physiological measurements in the water. This makes the constant monitoring of subjects/patients difficult during swimming exercises. Secondly, unlike walking or cycling, swimming requires skills and techniques in order to achieve a proper exercise intensity, and many at-risk populations may not be able to exercise at such a prescribed exercise intensity. From an experimental standpoint, this would necessitate an initial training or skill acquisition phase to introduce naive sedentary subjects into a swimming training programme, resulting in a longer study period and greater study expense. Thirdly, swimming had been discouraged or cautiously prescribed to patient populations in the past because of potential concerns associated with excess demands placed on the cardiovascular system.[24-26] For example, because immersion in cold water produces central volume expansion[27] as well as pressor responses,[24,25] it was thought that these haemodynamic changes would place extra stress on the limited cardiovascular reserves of cardiac patients. However, a number of studies have demonstrated that swimming can be performed as safely as other exercise modes, including walking and cycling, as there are no differences in exercise-induced angina, STsegment changes or arrhythmias between landbased exercise (e.g. walking and cycling) and water-based exercise (e.g. swimming), even in patients with cardiovascular disease.[28-31] 3. Swimming and Coronary Heart Disease Risk Factors The concept of risk factors for cardiovascular disease was originally introduced by the Framingham Heart Study and now serves as the cornerstone of the prevention of CHD.[32] Regular land-based physical activity (e.g. walking and running) has well established benefits for ª 2009 Adis Data Information BV. All rights reserved.
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reducing the risk of CHD and stroke, and is the first-line approach for preventing and treating various CHD risk factors.[3-5] Does water-based exercise (i.e. swimming) confer similar cardiovascular benefits as land-based physical activity? In this section, we review and evaluate the past research, including our own,[33-40] conducted in the area of regular swimming and key risk factors for CHD. The established CHD risk factors we address are maximal aerobic capacity, arterial blood pressure, blood lipids and lipoproteins, carbohydrate metabolism and insulin sensitivity, and bodyweight and fatness. Information derived from both cross-sectional and interventional studies is presented to provide more comprehensive views on this topic. 3.1 Maximal Aerobic Capacity
Maximal aerobic capacity is widely known as a primary factor in predicting endurance exercise performance and is an important indicator of physiological functional capacity.[41,42] It is also established that reduced maximal aerobic capacity, as estimated by either maximal oxygen con. sumption (VO2max) or the time to exhaustion in graded treadmill exercise tests, is an independent risk factor for cardiovascular and all-cause mortality.[43,44] Moreover, lower maximal values are associated with increased risks for disability[45] and reductions in cognitive function[46] and quality of life.[45] A greater maximal aerobic capacity is the hallmark of endurance-trained athletes, including runners and cyclists.[42,47] Even though most swimming events last 20% lower than that of runners, although its value was significantly greater than their sedentary peers a lack of transfer in (figure 1).[38,55] Obviously, . the training effects on VO2max between swimming (performed in prone or supine posture in the water) and running (performed in upright posture on land) is attributed to the principles of specificity of training and has been reviewed in detail elsewhere.[40] Thus, the available evidence indicates that the effects of regular swimming do not appear to manifest in the conventional measures of maximal aerobic capacity that have been associated with reduced risk of CHD.[43,44] Currently, it is not known whether having a
p < 0.0001
p < 0.001
. VO2max (mL/kg/min)
50 p < 0.001
40 30
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30.7 23.2
10 0 Controls
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. Fig. 1. Maximal oxygen consumption (VO2max) of postmenopausal runners, swimmers and sedentary controls (reproduced from Parker Jones et al.,[38] with permission from Wiley-Blackwell).
ª 2009 Adis Data Information BV. All rights reserved.
. high VO2max in swimming is cardioprotective. However, as described below, an epidemiological study suggests otherwise.[56] 3.2 Arterial Blood Pressure
Hypertension poses a major public health problem as the most prevalent vascular disease. Because of the side effects and cost of hypertensive drugs, non-pharmacological treatment, including regular exercise, is the first-line approach universally recommended for hypertension.[4,6,57] Land-based exercise training in patients with essential hypertension decreases blood pressure significantly, with systolic and diastolic blood pressure reductions averaging 11 and 8 mmHg, respectively.[4,58-60] Exercise training performed with cycling and walking appears to produce a similar magnitude of hypotensive effects.[61] To the best of our knowledge, there has been no direct comparison of swim training and other exercise modes on the efficacy for lowering blood pressure in patients with hypertension. Moreover, very few studies have been conducted to evaluate the potential hypotensive effects of regular swimming. Arterial blood pressure is known to increase during exercise. Compared with that during walking/jogging, average arterial blood pressure tends to be greater during swimming at the same heart rate values.[62] Cross-sectional comparisons indicate that swimmers tend to have chronically higher blood pressure at rest than other endurance athletes.[63-65] Moreover, a recent intervention study, in which previously sedentary normotensive older women were randomized into either a 6-month walking or swimming training programme, suggests that swimming may bring unfavourable, rather than beneficial, effects on blood pressure.[66] In the first study to date to evaluate the relative efficacy of swimming and walking exercise on blood pressure, these investigators found small but significant increases (rather than decreases) in both systolic and diastolic blood pressure (»D4 and D2 mmHg) after 6 months of swim training, whereas no changes in blood pressure were observed in the walking training group. These observations are certainly surprising, but the interpretation of Sports Med 2009; 39 (5)
Swimming Exercise and Cardiovascular Risk Factors
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Systolic BP (mmHg)
their data is difficult because of several methodological issues. In this study, average blood pressure values at the start of the interventions were 116/67 mmHg (completely ‘normal’ blood pressure). The beneficial effects of regular exercise on blood pressure are more likely to be manifested in human populations with elevated blood pressure. These low baseline blood pressure values may also explain why the researchers did not observe any hypotensive effects of walking training that have been previously reported in the literature.[4,58,67-70] It is understandable that a non-exercising sedentary control group (i.e. time control) was not included, because the stated aim was to compare the effects of swimming and walking on blood pressure. However, a lack of a time control group makes it difficult to determine whether the increase in blood pressure observed in the swimming training group was due to spontaneous changes in blood pressure. Taken together, these previous studies cast some doubts on the exercise recommendations/guidelines promoting regular swimming as an exercise modality of choice. Current exercise recommendations to include swimming for lowering blood pressure are based primarily on the results of a small-scale study in which 12 adults with essential hypertension underwent a 10-week swim training programme.[34] We found that swim training produced a significant reduction in systolic blood pressure whereas no significant changes in blood pressure were observed in the sedentary control group (figure 2).[34] However, the relative magnitude of the blood pressure reduction observed after swim training was slightly smaller than that typically reported for land-based physical activity. Studies using equivalent training programmes (of similar intensity, frequency and duration) but employing walking/jogging and cycling, reported 11 and 8 mmHg reductions in resting systolic and diastolic blood pressures, respectively.[4,58-60] The reductions in systolic and diastolic blood pressures observed in the swim training study averaged 7 and 3 mmHg, respectively.[34] Clearly, more studies are needed to answer the questions regarding the hypotensive effects of swimming exercise in patients with hypertension.
381
150
*
140
130
120 Before
After Swim training
Fig. 2. Reductions in arterial blood pressure (BP) after swim training intervention in patients with essential hypertension.[34] * p < 0.05 vs before swim training (reproduced with permission from Lippincott Williams & Wilkins).
3.3 Blood Lipids and Lipoproteins
Dyslipidaemia has long been acknowledged as a major risk factor in the development of atherosclerosis and CHD.[32] The effects of regular exercise on lipoprotein metabolism have been widely studied, and a number of indepth narrative reviews and meta-analyses have been published.[71] These studies conclude that the most consistent findings associated with exercise training are an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglyceride concentrations.[71] Unfortunately, swim training studies have not been included in these analyses, due primarily to a lack of well controlled studies in this area. Yet swimming is specifically mentioned as a recommended form of physical activity when the exercise guidelines for dyslipidaemia are promulgated. In most cases, similar to other CHD risk factors, findings of land-based exercise studies are unjustifiably extrapolated to swimming. Does the available evidence conducted in this area support such a notion? Considering that an acute (single) bout of swimming exercise elevates HDL-C levels following exercise,[72] it is reasonable to hypothesize that regular (repeated bouts of) swimming would chronically increase HDL-C concentrations similar to other land-based exercise modes.[71] Sports Med 2009; 39 (5)
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Most of the information available in this area comes from cross-sectional comparisons of swimmers with sedentary controls and other athletic populations. In studies involving age-group swimmers and collegiate swimmers, HDL-C levels were similar or somewhat lower than their age-matched sedentary counterparts.[73-75] In healthy postmenopausal women, we also demonstrated that HDL-C of swimmers was not different from their sedentary counterparts.[35] Longitudinal or interventional studies are consistent with these cross-sectional findings. In a season-long follow-up study, in which male collegiate swimmers were followed for 25 weeks, mean levels of HDL-C remained stable throughout the season in spite of significant changes in swim training volume.[73] We have also reported that a short-term supervised swim training did not result in significant increases in HDL-C concentrations in previously sedentary, obese middle-aged adults.[33] Thus, the available evidence is not consistent with the idea that regular swimming is associated with favourable levels of HDL-C. An interesting collective observation from the cross-sectional studies is that middle-aged and older swimmers demonstrate lower total cholesterol as well as low-density lipoprotein cholesterol (LDL-C) values than their sedentary counterparts, and in some cases the values are even lower than the age-matched runners.[35,76,77] The lower total cholesterol and LDL-C concentrations are not typically observed in land-based exercisetrained athletes and appear to be unique to swimmers. These cross-sectional studies need to be confirmed with a randomized, controlled, interventional study, but our short-term swim training study exhibited a trend for total cholesterol and LDL-C to decrease by »10% following the training in obese hypertensive subjects.[33] 3.4 Carbohydrate Metabolism and Insulin Sensitivity
Patients with diabetes mellitus exhibit markedly increased risks of developing all forms of cardiovascular disorders affecting the heart, brain and peripheral tissues. The underlying ª 2009 Adis Data Information BV. All rights reserved.
metabolic impairments in type 2 diabetes are attributed to defects in insulin-mediated glucose disposal (insulin resistance) and impaired secretion of insulin by pancreatic b cells. Insulin resistance typically precedes the onset of type 2 diabetes and is also a hallmark in the metabolic syndrome, which involves abdominal obesity, dyslipidaemia and hypertension. It has become increasingly recognized that the increasing prevalence of obesity and a sedentary lifestyle (or inactivity) are two key contributors to the rising epidemic of type 2 diabetes.[78] In epidemiological studies, the amount of daily aerobic exercise (primarily walking) is significantly and inversely associated with the risk/incidence of type 2 diabetes.[78,79] Likewise, intervention studies have demonstrated that exercise training, incorporating walking and jogging can normalize glucose tolerance by reducing insulin resistance in patients with type 2 diabetes.[80] As many diabetic patients are obese, swimming may be an ideal form of exercise for these patients. However, surprisingly few studies are available to evaluate the impact of regular swimming on glycaemic control in humans. We have previously demonstrated that the fasting plasma concentration of insulin was lower and insulin sensitivity, as determined from a frequently sampled intravenous glucose tolerance test and Bergman’s minimal model, was greater in postmenopausal swimmers compared with their age-matched sedentary controls (figure 3).[35] The level of insulin sensitivity achieved by the swimmers was not different from the runners, who were matched for age, training volume and exercise performance levels.[35] Interestingly, the high level of insulin sensitivity was achieved in swimmers even though swimmers had significantly higher bodyweight and body fatness than runners. In an exercise training intervention study involving young girls with type 1 diabetes, 14 weeks of swimming twice a week produced a significant reduction in the concentration of haemoglobin A1c, an indicator of average glucose load over the past several months.[81] Similarly, a long-term (2 years) exercise programme incorporating swimming resulted in a significant reduction in glycosylated haemoglobin in middle-aged women Sports Med 2009; 39 (5)
Swimming Exercise and Cardiovascular Risk Factors
Insulin sensitivity (×10−4 min/µU/mL)
10
* 8
*
6
4
2
0 Sedentary
Swimmers
Runners
Fig. 3. Insulin sensitivity of postmenopausal runners, swimmers and sedentary controls.[35] * p < 0.05 vs sedentary controls (reproduced with permission from Elsevier).
with type 2 diabetes, although the number of subjects was very small (n = 5).[82] Unfortunately, in both of these studies a time-control group was not included and their measurement stability over the training intervention period was not established. Nevertheless, the available evidence is consistent with the notion that regular swimming is associated with better glycaemic control. 3.5 Bodyweight and Body Composition
Until recently, the association between obesity and CHD was viewed as indirect through common covariates such as diabetes. Longitudinal studies, however, demonstrated that obesity is an independent predictor of CHD.[83] In general, increased physical activity, more specifically aerobic (endurance) exercises, is associated with maintenance of healthy levels of bodyweight and adiposity.[84] As described above, the daily training routine that swimmers perform is considered to be aerobic endurance training in nature. Given this, trained swimmers should exhibit low body fat levels similar to runners and cyclists. However, competitive swimmers tend to have higher body fat values compared with other endurance athletes[35,85,86] (although their values are lower than their sedentary peers[87]). This trend is more pronounced when ultra-endurance athletes in both running and swimming are compared.[88] In marked contrast to very low adiposity values frequently reported in ª 2009 Adis Data Information BV. All rights reserved.
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ultra-endurance runners, ultra-endurance (channel) swimmers exhibit substantially higher body mass index values (27–30 kg/m2).[88,89] Although a higher body fat percentage may be a requisite phenotype for success in swimming the English channel in cold water, as fat storage serves as insulation,[89] observing such high adiposity in ultraendurance athletes, who spend a considerable amount of time in high energy-expending activities, is certainly surprising. Higher body fat in swimmers may be an adaptive response to daily swimming routine, as a greater amount of body fat acts to enhance buoyancy and economy during distance swimming. At present, few studies have addressed the effects of swimming exercise intervention on bodyweight and body fat. A randomized, controlled study has reported that with 6 months of exercise intervention, young and middle-aged obese women who were assigned to walking or cycling lost »10% of initial bodyweight whereas those assigned to swimming experienced no change in bodyweight.[90] Although this is the only randomized, controlled study to address the relative efficacy of swimming to reduce body fat in obese subjects, exercise stimuli were not monitored and it is not clear how much swimming was performed by the subjects. However, the results of this study are consistent with a short-term swim intervention study showing that a closely supervised swimming programme did not result in a loss of bodyweight or body fat.[33] Additionally, a long-term study of swimming for 40 minutes a day three times a week for 2 years in middle-aged men also failed to demonstrate changes in bodyweight.[91] A recent epidemiological study has assessed how type/mode of regular physical activity, including swimming, is associated with weight gain attenuation over a 10-year period.[92] Although jogging, aerobic dancing and cycling were associated with the attenuation of age-related weight gain, swimming did not exert such effects.[92] Taken together, the available evidence indicates that long-term swimming may not be effective in reducing or maintaining bodyweight and body fatness. It is not clear why regular swimming is not associated with bodyweight or body fat reduction. Sports Med 2009; 39 (5)
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Resting metabolic rate (cal /h)
65
p = 0.001
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45
40
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40
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30 Premenopausal Postmenopausal sedentary sedentary
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Premenopausal Postmenopausal runners runners
Postmenopausal Postmenopausal swimmers runners
Fig. 4. Resting metabolic rates of premenopausal and postmenopausal female runners and swimmers and sedentary women[39] (reproduced with permission from the Endocrine Society). NS = not significant.
Theoretically, an increase in physical activity will increase total energy expenditure, thereby creating an overall negative energy balance if there is no compensation from increased caloric intake. Bodyweight and fat mass should, in turn, decrease in the long term. A study using doubly labelled water confirmed that the energy expenditure of swimmers is similar or even greater than other endurance athletes.[93] Additionally, swimmers demonstrate a similar level of baseline metabolic rate as runners (figure 4).[39] A current hypothesis is that exercise in cold water somehow stimulates appetite, thereby increasing energy intake in swimmers. In a randomized, crossover study design, young men exercised on a submerged cycle ergometer in 33C (neutral) and 20C (cold) water.[94] Although the energy expenditure between the two exercise conditions was kept at the same level, energy intake after exercise in cold water was 44% greater than that in neutral water.[94] In this context, it is interesting to note that swim-trained rats consume a greater amount of calories compared with runtrained rats,[10,11] and that energy intake of swimtrained rats increases as a function of decreasing water temperature in which rats exercised.[10] 4. Swimming and Mortality A number of epidemiological studies have reported that regular physical activity is associated with reduced risks of cardiovascular and allª 2009 Adis Data Information BV. All rights reserved.
cause mortality.[1,2,7] The primary modes of physical activity that have been addressed in these epidemiological studies are walking, jogging and running. To the best of our knowledge, only one epidemiological study has specifically addressed the association between regular swimming and risks of CHD.[56] As expected, both walking and running were significantly and inversely associated with CHD risk. However, such an association was not observed in regular swimmers.[56] Thus, at present, unlike land-based exercise activities, regular swimming is not associated with reduced risks of developing CHD. 5. Conclusions Since swimming is a rhythmic, dynamic form of endurance exercise involving a large muscle mass, it is a potentially useful alternative to landbased exercises insofar as the efficacy and safety of swimming can be assured. Swimming, however, is inherently different from land-based exercise in many respects due to water immersion and the prone body position. Physiological responses to swimming are affected by many factors, including hydrostatic pressure, facial immersion and high thermal conductivity of water. As a result, research findings obtained in land-based exercise training studies cannot be extrapolated simply to swimming. Available evidence indicates that regular swimming appears to exert beneficial effects on arterial blood pressure Sports Med 2009; 39 (5)
Swimming Exercise and Cardiovascular Risk Factors
and insulin sensitivity, while elevating the level of mood state.[36] However, the impacts of swimming on blood lipid profile, bodyweight and fatness, bone mineral density[95] and relative risk of developing CHD seem to be small or none. The available research studies using swimming exercise intervention are very limited. Clearly, further studies are warranted to establish the effects of regular swimming on CHD risks in humans. Acknowledgements No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.
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10. 11. 12.
13.
14.
15.
16.
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47. Pollock ML. The quantification of endurance training programs. In: Wilmore J, editor. Exercise and sports sciences reviews. Vol. 1. New York: Academic Press, 1973: 155-88 48. Houston ME, Wilson DM, Green HJ, et al. Physiological and muscle enzyme adaptations to two different intensities of swim training. Eur J Appl Physiol 1981; 46: 283-91 49. Magel JR, Faulkner JA. Maximum oxygen uptakes of college swimmers. J Appl Physiol 1967; 22 (5): 929-38 50. Holmer I, Lundin A, Eriksson BO. Maximum oxygen uptake during swimming and running by elite swimmers. J Appl Physiol 1974; 36 (6): 711-4 51. Magel JR, Foglia GF, McArdle WD, et al. Specificity of swim training on maximum oxygen uptake. J Appl Physiol 1975; 38 (1): 151-5 52. Holmer I, Astrand PO. Swimming training and maximal oxygen uptake. J Appl Physiol 1972; 33 (4): 510-3 53. Eriksson BO, Holmer I, Lundin A. Physiological effects of training in elite swimmers. In: Eriksson BO, Furberg B, editors. Swimming medicine IV. Baltimore (MD): University Park Press, 1978: 177-87 54. Gergley TJ, McArdle WD, DeJesus P, et al. Specificity of arm training on aerobic power during swimming and running. Med Sci Sports Exerc 1984; 16 (4): 349-54 55. Koda M, Mutoh Y, Higuchi M, et al. Aerobic work capacity of Japanese masters swimmers. Coaching Sport Sci J 1994; 1 (1): 16-8 56. Tanasescu M, Leitzmann MF, Rimm EB, et al. Exercise type and intensity in relation to coronary heart disease in men. JAMA 2002; 288 (16): 1994-2000 57. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157 (24): 2413-46 58. Tanaka H, DeSouza CA, Seals DR. Exercise and hypertension in older adults. In: Tanaka H, Shindo M, editors. Exercise for preventing common diseases. Tokyo: SpringerVerlag, 1999: 45-50 59. Hagberg JM, Park JJ, Brown MD. The role of exercise training in the treatment of hypertension: an update. Sports Med 2000; 30 (3): 193-206 60. Wallace JP. Exercise in hypertension: a clinical review. Sports Med 2003; 33 (8): 585-98 61. Kingwell B, Jennings GL. Effects of walking and other exercise programs upon blood pressure in normal subjects. Med J Aust 1993; 158: 234-8 62. Holmer I, Stein EM, Saltin B, et al. Hemodynamic and respiratory responses compared in swimming and running. J Appl Physiol 1974; 37 (1): 49-54 63. Cureton Jr TK. Physical fitness appraisal and guidance. St Louis (MO): CV Mosby, 1947 64. Jost J, Weiss M, Weicker H. Sympathoadrenergic regulation and the adrenoceptor system. J Appl Physiol 1990; 68 (3): 897-904 65. Marconnet P, Slaoui F, Gastaud M, et al. Preexercise, exercise and early post exercise arterial blood pressure in young competitive swimmers versus non swimmers. J Sports Med 1984; 24: 252-8
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66. Cox KL, Burke V, Beilin LJ, et al. Blood pressure rise with swimming versus walking in older women: the Sedentary Women Exercise Adherence Trial 2 (SWEAT 2). J Hypertens 2006; 24 (2): 307-14 67. Ishikawa K, Ohta T, Zhang J, et al. Influence of age and gender on exercise training-induced blood pressure reduction in systemic hypertension. Am J Cardiol 1999; 84 (2): 192-6 68. Ishikawa-Takata K, Ohta T, Tanaka H. How much exercise is required to reduce blood pressure in essential hypertensives: a dose-response study. Am J Hypertens 2003; 16 (8): 629-33 69. Tanaka H, Reiling MJ, Seals DR. Regular walking increases peak limb vasodilatory capacity of older hypertensive humans: implications for arterial structure. J Hypertens 1998; 16: 423-8 70. Fagard R, Amery A. Physical exercise in hypertension. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press, 1995: 2669-81 71. Durstine JL, Grandjean PW, Cox CA, et al. Lipids, lipoproteins, and exercise. J Cardiopulm Rehab 2002; 22 (6): 385-98 72. Ohkuwa T, Itoh H. High density lipoprotein cholesterol following anaerobic swimming in trained swimmers. J Sports Med Phys Fitness 1993; 33: 200-2 73. Barr SI, Costill DL, Fink WJ, et al. Effect of increased training volume on blood lipids and lipoproteins in male collegiate swimmers. Med Sci Sports Exerc 1991; 23 (7): 795-800 74. Sgouraki E, Tsopanakis A, Tsopanakis C. Acute exercise: response of HDL-C, LDL-C lipoproteins and HDL-C subfractions levels in selected sport disciplines. J Sports Med Phys Fitness 2001; 41 (3): 386-91 75. Schnabel A, Kindermann W. Effect of maximal oxygen uptake and different forms of physical training on serum lipoproteins. Eur J Appl Physiol 1982; 48: 263-77 76. Higuchi M, Ishii K, Yoshitake Y, et al. Plasma lipoprotein profile in Japanese middle-aged swimmers. In: Miyashita M, Mutoh Y, Richardson AB, editors. Medicine and science in aquatic sports. Basel: Karger, 1994: 193-8 77. Higuchi M, Tamai T, Kobayashi S, et al. Plasma lipoprotein and apolipoprotein profiles in aged Japanese athletes. In: Sato Y, Poortmans J, Hashimoto I, et al., editors. Integration of medical and sports sciences: medical sports science. Basel: Karger, 1992: 126-36 78. Weinstein AR, Sesso HD, Lee IM, et al. Relationship of physical activity versus body mass index with type 2 diabetes in women. JAMA 2004; 292 (10): 1188-94 79. Hu FB, Sigal RJ, Rich-Edwards JW, et al. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA 1999; 282 (15): 1433-9 80. Holloszy JO, Schultz J, Kusnierkiewicz J, et al. Effects of exercise on glucose tolerance and insulin resistance. Acta Med Scand Suppl. 1986; 711: 55-65
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81. Sideraviciute S, Gailiuniete A, Visagurskiene K, et al. The effect of long-term swimming program on glycemic control in 14–19 year aged healthy girls with type 1 diabetes mellitus. Medicina 2006; 42 (6): 513-9 82. Makita S, Nohara R, Uehara H, et al. Training program incorporating swimming for patients with mild diabetes mellitus. In: Miyashita M, Mutoh Y, Richardson AB, editors. Medicine and science in aquatic sports. Basel: Karger, 1994; 76-81 83. Eckel RH. Obesity and heart disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1997; 96: 3248-50 84. Hill JO, Commerford R. Physical activity, fat balance, and energy balance. Int J Sport Nutr 1996; 6: 80-92 85. Flynn MG, Costill DL, Kirwan JP, et al. Fat storage in athletes: metabolic and hormonal responses to swimming and running. Int J Sports Med 1990; 11 (6): 433-40 86. Housh TJ, Thorland WG, Johnson GO, et al. Body composition variables as discriminators of sports participation of elite adolescent female athletes. Res Quart 1984; 55 (3): 302-4 87. Vaccaro P, Ostrove SM, Vandervelden L, et al. Body composition and physiological responses of masters female swimmers 20 to 70 years of age. Res Quart 1984; 55 (3): 278-84 88. Pugh LGCE, Edholm OG, Fox RH, et al. A physiological study of channel swimming. Clin Sci 1960; 19: 257-73 89. Pugh LGC, Edholm OG. The physiology of channel swimmers. Lancet 1955; ii: 761-8 90. Gwinup G. Weight loss without dietary restriction: efficacy of different forms of aerobic exercise. Am J Sports Med 1987; 15 (3): 275-9 91. Kasch FW. Physiological changes with swimming and running during two years of training. Scand J Sports Sci 1981; 3 (1): 23-6 92. Littman AJ, Kristal AR, White E. Effects of physical activity intensity, frequency, and activity type on 10-y weight change in middle-aged men and women. Int J Obes (Lond) 2005; 29 (5): 524-33 93. Jones PJ, Leitch CA. Validation of doubly labeled water for measurement of caloric expenditure in collegiate swimmers. J Appl Physiol 1993; 74 (6): 2909-14 94. White LJ, Dressendorfer RH, Holland E, et al. Increased caloric intake soon after exercise in cold water. Int J Sport Nutr Exerc Metab 2005; 14: 38-47 95. Taaffe DR, Snow-Harter C, Connolly DA, et al. Differential effects of swimming versus weight-bearing activity on bone mineral status of eumenorrheic athletes. J Bone Miner Res 1995; 10 (4): 586-93
Correspondence: Dr Hirofumi Tanaka, Department of Kinesiology and Health Education, The University of Texas at Austin, 1 University Station (D3700), Austin, TX 78712, USA. E-mail:
[email protected] Sports Med 2009; 39 (5)
REVIEW ARTICLE
Sports Med 2009; 39 (5): 389-422 0112-1642/09/0005-0389/$49.95/0
ª 2009 Adis Data Information BV. All rights reserved.
Exercise and Fatigue Wim Ament1 and Gijsbertus J. Verkerke2,3 1 Department of Biometrics, Faculty of Health and Technology, Zuyd University, Heerlen, the Netherlands 2 Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 3 Department of Biomechanical Engineering, University of Twente, Enschede, the Netherlands
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Physiological Aspects of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Effects of Exercise on the Motor Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1 Biomechanical Consequences of the Accumulation of Metabolites within Muscle Fibres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2 Depletion of Glycogen Stores in Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.3 The Effect of Exercise on Muscle Membrane Structures: Excitation-Contraction Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.4 The Neuromuscular Junction and the Peripheral Nerve. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.5 Differentiation of Muscle Fibre and Motor Unit Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Effects of Exercise on the Internal Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Effects of Exercise on the CNS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.1 Afferents and Motor Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2 Central and Peripheral Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.3 The Motor Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.4 The Core Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.5 Branched Chain Amino Acids and the Serotoninergic System . . . . . . . . . . . . . . . . . . . . . . . 1.3.6 The Role of Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.7 Brain Metabolism during Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Psychological Aspects of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Sensations Related to Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Rating Points of Exertion (Borg Scale) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 The Teleoanticipatory System and Other Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1 The Teleoanticipatory System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 The Central Governor Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 The Catastrophic Failure Model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4 Arguments against the Central Governor Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 The Effect of the Intensity of the Workload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Disease and Fatigue during Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Diseases in General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 General Aspects of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2 Cytokines and Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Some Effects of Anti-Inflammatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Vascular and Heart Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.6 Pulmonary Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.7 Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.2 Chronic Fatigue Syndrome and Overtraining Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Chronic Fatigue Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Overtraining Syndrome and the Neuroendocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Physical exercise affects the equilibrium of the internal environment. During exercise the contracting muscles generate force or power and heat. So physical exercise is in fact a form of mechanical energy. This generated energy will deplete the energy stocks within the body. During exercise, metabolites and heat are generated, which affect the steady state of the internal environment. Depending on the form of exercise, sooner or later sensations of fatigue and exhaustion will occur. The physiological role of these sensations is protection of the exercising subject from the deleterious effects of exercise. Because of these sensations the subject will adapt his or her exercise strategy. The relationship between physical exercise and fatigue has been the scope of interest of many researchers for more than a century and is very complex. The exercise intensity, exercise endurance time and type of exercise are all variables that cause different effects within the body systems, which in turn create different types of sensation within the subject’s mind during the exercise. Physical exercise affects the biochemical equilibrium within the exercising muscle cells. Among others, inorganic phosphate, protons, lactate and free Mg2+ accumulate within these cells. They directly affect the mechanical machinery of the muscle cell. Furthermore, they negatively affect the different muscle cell organelles that are involved in the transmission of neuronal signals. The muscle metabolites produced and the generated heat of muscle contraction are released into the internal environment, putting stress on its steady state. The tremendous increase in muscle metabolism compared with rest conditions induces an immense increase in muscle blood supply, causing an increase in the blood circulatory system and gas exchange. Nutrients have to be supplied to the exercising muscle, emptying the energy stocks elsewhere in body. Furthermore, the contracting muscle fibres release cytokines, which in their turn create many effects in other organs, including the brain. All these different mechanisms sooner or later create sensations of fatigue and exhaustion in the mind of the exercising subject. The final effect is a reduction or complete cessation of the exercise. Many diseases speed up the depletion of the energy stocks within the body. So diseases amplify the effect of energy stock depletion that accompanies exercise. In addition, many diseases produce a change of mind-set before exercise. These changes of mind-set can create sensations of fatigue and exercise-avoiding behaviour at the onset of an exercise. One might consider these sensations during disease as a feed-forward mechanism to protect the subject from an excessive depletion of their energy stocks, to enhance the survival of the individual during disease.
For more than a century, exercise-induced fatigue and exhaustion have been an area of interest for many physiologists. A comprehensive review, including history, is given by Gandevia.[1] ª 2009 Adis Data Information BV. All rights reserved.
Although most exercise-related studies focus on the neuromuscular system, in fact all organs are involved. Not only the neuromuscular system but other organs also react to the individual’s exercise Sports Med 2009; 39 (5)
Exercise and Fatigue
capacity. It is well known that this exercise capacity is reduced during illness. Chronic illness, such as end-stage renal failure, has an immense impact on exercise capacity. Fatigue caused by exercise is a common sensation, which everybody has experienced. During exercise the workload may create such an intense sensation that one has to reduce the workload or even stop the exercise. Any physical exercise is an energy-consuming activity, which will sooner or later empty the energy stocks within our body. An unlimited consumption of these stocks without re-supply would have deleterious effects on our physical health. Therefore, the sensations of fatigue and exhaustion are most likely essential for maintaining our physical integrity. The sensations of fatigue and exhaustion represent psychological entities, which will sooner or later introduce changes in behaviour. The accompanying physical and biochemical changes during exercise are physiological entities. The phenomena of fatigue and exhaustion during exercise are fields of interest of different scientific disciplines, especially physiology and psychology. The physical and biochemical changes during exercise are physiological effects. In exercise physiology these effects are defined as ‘fatigue’, and can be monitored objectively. However, ‘fatigue’ is also a psychological entity, which represents a subjective and mental variable. Besides fatigue, ‘exhaustion’ is another psychological entity that is related to physical exercise. Despite the constant motor output during exercise, the ‘sense of effort’ may increase gradually.[2] Sometimes this sense of effort can be so intense that it topples one’s willpower to maintain the motor output and forces the subject to reduce or even stop his/her workload. In this article, this moment is defined as ‘exhaustion’. This is in contrast to the definition stated during the CIBA Foundation Symposium 82 of 1981 (Chairman RHT Edwards),[3] where ‘fatigue’ was defined as the moment when a subject is unable to maintain the required muscle contraction or performed workload. In this article ‘exhaustion’ has the same quality as the definition of ‘fatigue’ given at the CIBA Symposium. The ‘sense of effort’ is not the same as the ‘sense of perceived exertion’. The ª 2009 Adis Data Information BV. All rights reserved.
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sense of perceived exertion reflects more or less all the subjective sensations accompanied during an exercise performance. Borg[4] has introduced a psychophysical ratio scale for perceived exertion. In exercise, the performed motor output can be measured. Motor output is the mechanical output produced by the contractile properties of the skeletal muscle, which can be measured objectively as contraction force (in newtons [N]) or as power (in watts [W]). In this article the neuronal output of the motor cortex is defined as motor drive. The motor drive of the motor cortex is the final result of many centres in the CNS, which act on the motor cortex. These centres are situated in the cerebral cortex, in subcortical nuclei and in nuclei situated in the brain stem. The CNS and the motor units together form the neuromuscular system. For a proper functioning of this system, it is embedded in the internal environment, which has a physical and chemical equilibrium. This equilibrium, the steady state of the internal environment, is maintained by the other organs. Exercise affects the neuromuscular system as well as the internal environment at many levels. Exercise is accompanied by psychological phenomena. Different types of exercise create different kinds of sensations. Furthermore, disease alters the exercise capacity. All these different aspects of exercise are reviewed in this article. A synopsis of the different causes is shown in table I.
1. Physiological Aspects of Exercise 1.1 Effects of Exercise on the Motor Unit 1.1.1 Biomechanical Consequences of the Accumulation of Metabolites within Muscle Fibres
The energy source for the contraction of muscle fibres (muscle cells) is adenosine triphosphate (ATP).[5,6] In the muscle cell, the major pathways for ATP production include:[6] 1. A rapid production of ATP from sarcoplasmic stores of creatine phosphate. 2. A somewhat slower production using anaerobic glycolysis. The enzymes and fuel (i.e. glycogen) for these reactions are located in the sarcoplasm. Sports Med 2009; 39 (5)
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Table I. Overview of possible sites of exercise-associated fatigue I. Peripheral fatigue A. Exercise-related changes in the internal environment During exercise workloads above the point of increased blood lactate accumulation (OBLA), changes in the internal environment (blood, extracellular fluid) include: 1. Accumulation of lactate and hydrogen ions (protons). The accumulation of hydrogen ions is partly buffered such that there is an increased liberation of carbon dioxide from bicarbonate. As a result, the respiratory quotient will increase 2. Accumulation of ammonia 3. Accumulation of heat, leading to increased sweat secretion. The loss of water may lead to dehydration B. Exercise-related changes within muscle fibres 1. Accumulation of Pi (inorganic phosphate) in the sarcoplasm, causing a decrease in contractile force due to an inhibition of cross-bridge interactions 2. Accumulation of H+ ions in the sarcoplasm, also causing a decrease in contractile force due to an inhibition of cross-bridge interactions. In addition, the accumulation of H+ ions may cause a depression in calcium re-uptake in the sarcoplasmic reticulum. This might be the main cause for the lengthened relaxation time after fatiguing contractions 3. Accumulation of Mg2+ ions in the sarcoplasm. Mg2+ counteracts the Ca2+ release from the sarcoplasmic reticulum 4. Inhibition of the Ca2+ release of the sarcoplasmatic reticulum by accumulation of Pi (see point 1). The Ca2+ release is inhibited by precipitation of calcium phosphate within the lumen of the sarcoplasmatic reticulum and by phosphorylation of the Ca2+ release channels 5. Decline of glycogen stores and (in extreme cases) decline of blood glucose levels. Even a short-lasting decline of blood glucose might seriously interfere with CNS functions. A depletion of the glycogen stores leads, in a manner not well understood, to increased muscle fatigue 6. Decreased conduction velocity of action potentials along the sarcolemma, probably as a result of exercise-associated biochemical changes in and around the muscle fibres. The drop in conduction velocity is reflected in the EMG (change of frequency content) but has no known immediate effect on the muscular force production 7. Increased efflux of potassium ions (K+) from muscle fibres. The increase in potassium in the lumen of the t-tubuli may lead to a block of the tubular action potential and, hence, less force due to a depression of excitation-contraction coupling 8. Neuromuscular synaptic transmission may become blocked; however, this seems to be a factor mainly of importance in disease (myasthenia gravis) II. Central fatigue 1. The conduction of axonal action potentials may become blocked at axonal branching sites, leading to a loss of muscle fibre activation. The relative importance of this factor is unknown 2. The motor neuronal drive might be influenced by reflex effects from muscle afferents. Thus, central fatigue effects might, to some extent, be compensated for by mechanoreceptor reflexes (types IA and II from muscle spindles; type IB from Golgi tendon organs) 3. Stimulation of type III and IV nerves (chemo- and nociceptive afferents) induces a decrease in motor neuron firing rate and an inhibition of the motor cortex output 4. The excitability of cells within the cerebral motor cortex might change during the course of maintained motor tasks, as suggested by measurements using transcranial magnetic stimulation 5. The synaptic effects of serotoninergic neurons might become enhanced, causing an increased sense of tiredness and ‘fatigue’. This may occur as a result of an increased influx into the brain of the serotonin precursor tryptophan. During prolonged exercise, such an increased influx of tryptophan may result from an exercise-evoked decrease in the blood concentration of BCAAs 6. Exercise-induced release of cytokines. IL-6 induces sensations of fatigue and IL-1 induces sickness behaviour in animals. In many diseases the production of these cytokines is enhanced BCAAS = branched-chain amino acids; EMG = electromyograph; IL = interleukin; OBLA = onset of blood lactate accumulation; Pi = inorganic phosphate.
3. A slower but very effective production of ATP using aerobic pathways for glycolysis and fat metabolism by the mitochondria. Independent of which pathway is dominating, muscle contractions will always be associated with an increase in adenosine diphosphate (ADP) and inorganic phosphate (Pi) production (e.g. from the cross-bridge cycle itself). During intense ª 2009 Adis Data Information BV. All rights reserved.
contractions, the accumulation of Pi can even be measured in vivo using nuclear magnetic resonance (NMR) spectroscopy.[7-10] In addition, anaerobic glycolysis leads to an increased production of hydrogen ions (H+) and a measurable decrease of intra- and extracellular pH. The concentration of these three metabolites (ADP, Pi and H+) will be particularly increased in Sports Med 2009; 39 (5)
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contractions of high force and power, and they all have direct effects on the efficiency of the crossbridge interactions. The efficiency of the crossbridge interaction is estimated by two factors: (i) the duration of attachment and detachment of the actin and myosin filaments during the crossbridge cycle; and (ii) the speed of the cross-bridge cycle (see figure 1). The rate-limiting step in the cross-bridge cycle is the release of Pi, which is the step from A-M-ADP~Pi to A-M-ADP.[12] An increase in [H+] reduces isometric contraction force[13] and decreases the period of filament attachment.[14] Perhaps, an increase in [H+] enhances the binding of ATP to the actin-myosin complex during the attachment phase of the cross-bridge cycle, which in turn speeds up the uncoupling of the actin and myosin filaments.[15] Cooke et al.[16] found a decrease in contraction velocity during increasing concentrations of [H+]. In her review, Myburgh[17] debates to what extent this decrease in contraction velocity is caused by the low temperature (10C) in which these experiments were performed. Westerblad et al.[18] found no decrease in contraction velocity at temperatures of 30C. Normally, skeletal muscle temperature is above 30C. Therefore, a drop in intramuscular pH during exercise has most likely no effect on contraction velocity under normal physiological circumstances. An increase in [ADP] slows down the period of attachment, but increases the isometric tension.[19,20] Accumulation of inorganic phosphate depresses isometric contraction force[21,22] and decreases myofilament ATPase turnover.[23] During isokinetic contraction experiments, an increase in [Pi] also induces a decrease in the myofilament ATPase turnover.[24] Figure 1 provides a schematic outline of the cross-bridge cycle. In fact, the increase in concentrations of Pi and H+ gives a reduction of the force-producing capability of the filaments. In turn, the increase in ADP concentration increases force production and also reduces cross-bridge cycle velocity. 1.1.2 Depletion of Glycogen Stores in Muscles
Exercise intensities below the point of onset of blood lactate accumulation (OBLA) can be maintained for long periods (see section 1.2). The ª 2009 Adis Data Information BV. All rights reserved.
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limiting factor for these endurance exercises is the availability of glucose.[25,26] The concentration of blood glucose is maintained at constant levels and is regulated by the interaction of many hormones.[27] Glucose uptake by exercising muscles is mediated by glucose transporters.[28] Nitric oxide (NO) plays a role in the uptake of glucose by exercising muscles. Muscle cells contain NO-synthetase.[29] Most likely, NO-synthetase is Effects of [ ]: Pi
F
v=
ADP
F
v
H+
F
v=
Filament detachment period
M-ATP A-M-ATP M-ADP-Pi
H+ A-M
A-M-ADP∼Pi Pi A-M-ADP A-M-ADP
Filament displacement ADP
Filament attachment period Fig. 1. Model of the cross-bridge cycle according to Cooke.[11] The effect changes in concentration of H+, adenosine diphosphate (ADP) and Pi during the cross-bridge cycle is shown schematically. The box at the right side of the figure shows the effects of these changes in concentration. A = actin; A-M = the actin-myosin complex; A-MADP = the actin-myosin-ADP complex; A-M-ADP~Pi = actin-myosinADP~Pi complex (~Pi is the energy rich chemical bonding used during the filament displacement); A-M-ATP = the actin-myosin-ATP complex; F = force generated by the filaments; M = myosin; M-ADPPi = myosin-ADP-Pi complex after ATP hydrolysis; M-ATP = myosinATP complex; Pi = inorganic phosphate; v = cross-bridge cycle velocity; › / fl indicates increase/decrease in concentration. The fat arrow indicates the displacement of the actin-myosin filaments, which is the power-generating period of the cross-bridge.
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activated by the calcium increase in the sarcoplasm during muscle contraction. The effect is that the contracting muscle releases NO, which increases the activity of the glucose transporter, resulting in an increase in glucose uptake. It has been demonstrated that administration of local NO synthetase blockers decreases glucose uptake by the exercising muscles.[30] During endurance exercise, the intracellular glycogen stores decrease little by little and the muscle tissue gradually increases its consumption of blood glucose. Finally, the availability of glucose is smaller than the glucose consumption and the concentration of blood glucose may even decrease.[27] This usually occurs at 1–2 hours after the onset of exercise: in marathon running this occurs after about 30 km, and the athlete experiences this as ‘the hitting of a wall’. The trigger for these sensations may be a direct reaction of the brain to the decreased concentration of blood glucose; brain tissue needs a minimum amount of continuous glucose supply for normal function.[31] Athletes try to avoid the decrease in blood glucose by consuming glucose-containing drinks during the race.[32] 1.1.3 The Effect of Exercise on Muscle Membrane Structures: Excitation-Contraction Coupling
Cross-bridge interactions and force production are started as a result of a sequence of events leading to the release of calcium ions from the sarcoplasmic reticulum (SR). This sequence of events is referred to as the ‘excitation-contraction coupling’ (EC-coupling). A decreased efficiency or block of EC-coupling will lead to a decrease or disappearance of contractile force. Such changes play an important role in muscle fibre fatigue and associated phenomena. The sarcolemmal action potentials of many simultaneously active muscle fibres can be recorded with extracellular electrodes on or in a muscle, i.e. using electromyographic (EMG) techniques. The amplitude of sarcolemmal action potentials (and of the EMG) may decrease during prolonged activation,[33-35] perhaps partly as a result of changes in the transmembrane electrolyte concentrations (efflux of potassium, influx of sodium).[36] Another commonly seen effect of ª 2009 Adis Data Information BV. All rights reserved.
intense activity is a decrease in the propagation velocity of the action potentials along the sarcolemmae.[37,38] As a result, the frequency spectrum of the EMG shifts to lower frequencies, a change that has often been interpreted as a sign of muscle fatigue.[39] Our investigations support this opinion. During a treadmill exercise load of 18 W/kg bodyweight and an endurance time ranging from 31 to 162 .seconds (far above the maximum oxygen uptake [VO2max], see also figure 4) we found a decrease in the EMG frequency spectrum.[40] However, at a workload of 12.4 W/kg bodyweight and during a cycle ergometer exercise above the lactate threshold we found no change.[41,42] These findings suggest that during dynamic exercise, local changes within the muscle cell occur. only at supramaximal workloads far above the VO2max. At these supramaximal workloads, ATP turnover might be so intense that accumulation of muscle metabolites within the cell could occur during the exercise. The frequency content of the EMG also depends on other factors, such as the degree of synchronization of the various muscle fibre action potentials.[43,44] The EMG, especially the integrated EMG, might increase during sustained intermittent exercise at submaximal isometric contraction force.[45-47] Two mechanisms could contribute to this increase in the EMG: (i) an increase in the motor neuron discharge frequency;[46,47] and (ii) the increase in the pool of recruited motor neurons.[47] Changes in transmembrane electrolyte concentration are particularly prone to appear along the very thin t-tubuli and, as a result, action potential propagation along these tubuli seems to become gradually more blocked during intense activity,[48,49] leading to an inhibition of muscle fibre activation. It is not known to what extent the accumulation of muscle metabolites (ADP, Pi, H+) affects the activity of the ion pumps of the sarcolemma, which in turn can affect action potential propagation alongside the sarcolemma. In fatigued muscles, the speed of force relaxation at the end of a contraction is typically slowed down (increased relaxation time[50]), probably largely as a result of a decreased rate of Ca2+ transport back into the SR. Such an inhibition of the SR Ca2+ pump might be caused by the Sports Med 2009; 39 (5)
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increased concentration of H+ ions (decreased pH) that occurs during intense muscle activity. Subjects with a myophosphorylase deficiency (McArdle’s disease) are unable to break down muscle glycogen and they hardly develop any decrease in pH during muscle activity.[51-53] Cady et al.[54] demonstrated that their relaxation time was also less affected than that of normal subjects. Mg2+ ions play an important role in the functioning of the SR. During muscle activation, an increased Mg2+ concentration in the sarcoplasm reduces the Ca2+ fluxes across the membrane of the SR.[55,56] Westerblad and Allen[57] demonstrated increased intracellular Mg2+ concentrations during exercise and concluded that this might cause a decrease in muscle force. During activity, the concentration of free Mg2+ in the sarcoplasm increases, partly because Mg2+ ions are bound to the ATP molecules and to voltage sensors of the SR. Activation of these voltage sensors removes the Mg2+ ion and opens the Ca2+ channel.[55,56] During repeated tetanic stimulation, sarcoplasmatic (or myoplasm) Ca2+ concentration in the active skeletal muscle fibres increases within the first and decreases in the last period of stimulation. The maximum obtained Ca2+ concentrations are 1–2 mmol/L.[45,58] In fast-twitch (type II) muscle fibres this mechanism evolves faster than in slow-twitch (type I) fibres. The contraction force of these stimulated fibres shows a small decrease within the first period of tetanic stimulation,[45] which is caused by the increase of the sarcoplasmatic Pi concentration, which directly affects the cross-bridge interaction of the myofilaments (see section 1.1.1). Sarcoplasmatic Pi concentrations can increase from 1–5 mmol/L during rest conditions to 30–40 mmol/L during intense contraction.[58] The drop of muscle fibre contraction force at the end stage of the stimulation period is caused by an impaired Ca2+ release by the SR. One reason for this impaired Ca2+ release is the decline of the amplitude of the action potential across the sarcolemma. Another reason could be the effect of the relatively high sarcoplasmatic Pi concentration, which has two effects at the SR Ca2+ release. The first effect is ª 2009 Adis Data Information BV. All rights reserved.
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precipitation of calcium phosphate in the lumen of the SR. Through high sarcoplasmatic concentrations, Pi enters the lumen of the SR by a passive process via the chloride channels.[58] The Ca2+ concentration within the lumen of the SR is estimated at 1 mmol/L.[58] The solubility product of Ca(HPO4) is about 10-7–10-6, and the solubility of Ca(H2PO4)2 is a larger by a factor of 60.[59] So most likely Ca(HPO4) precipitates inside the lumen of the sarcoplasmatic reticulum, reducing the concentration of free Ca2+, which in turn reduces the Ca2+ concentration gradient between the lumen of the SR and the sarcoplasm. The other effect of the high sarcoplasmatic Pi concentration is phosphorylation of the Ca2+ release channels of the SR. These Ca2+ release channels are very large and complex polypeptide structures containing four tetramers, each of about 565 kDa.[60] The phosphorylation of these Ca2+ channels inhibits the SR Ca2+ release.[45,61] The increase of sarcoplasmatic Mg2+ during exercise[57] enhances the effect of Pi inhibition.[45] The final effect of the sarcoplasmatic increase of Pi concentration during persistent contraction is a drop in Ca2+ efflux by the SR. In vitro experiments suggest that caffeine releases this inhibition.[58] The ion shifts across the sarcolemma during exercise have consequences for the internal environment.[62] Action potentials (APs) are associated with the efflux of potassium and the influx of sodium. Sjøgaard et al.[63] found a net loss of 20 mmol potassium from maximally exercising muscles during a one-leg knee extension exercise. They estimated the mass of the contracting muscle at about 2.5 kg. After the exercise, they measured potassium concentrations up to 6.0–6.5 mmol/L in the femoral vein and up to 5.0–5.5 mmol/L in the femoral artery (normal values at rest 3.6 up to 4.8 mmol/L). During graded treadmill exercise until exhaustion, Busse and Maassen[64] found final arterial potassium levels of 5.5–6.0 mmol/L. After 1 minute of running at a maximal speed, Medbo and Sejersted[65] observed potassium concentrations exceeding 7 mmol/L in the femoral artery. Some viral infections are accompanied by myocarditis.[66,67] In most cases these viral forms of myocarditis are asymptomatic.[66] During the Sports Med 2009; 39 (5)
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influenza epidemic of 1957, Gibson et al.[68] showed that these infections can induce ECG changes. Of the 87 male students in the study who were infected by the influenza virus, five students showed ECG changes during illness and six during recovery. The ECGs of these infected students showed changes in T-wave and ST-segment elevations in the precordial leads. Based on these observations, one should take care with performing vigorous exercise during a common cold, because the sudden increases in plasma potassium during exercise might trigger unexpected cardiac pathology. In our exercise studies, volunteers who had symptoms of a common cold within 7 days prior to the study were excluded. 1.1.4 The Neuromuscular Junction and the Peripheral Nerve
The neuromuscular synapse has been the subject of many investigations in the context of peripheral fatigue (for a definition of peripheral fatigue, see section 1.3.2). The results of these investigations are somewhat inconsistent. Several authors found a decrease in the amount of released acetylcholine from the presynaptic nerve terminal during repetitive nerve stimulation.[69,70] Others observed signs of postsynaptic desensitization at the motor end-plate.[71] However, such changes do not mean that the transmission from nerve endings to muscle fibres becomes blocked; the respective postsynaptic potential (the endplate potential) normally has an amplitude largely exceeding the amplitude needed for eliciting a postsynaptic action potential. Bigland-Ritchie et al.[72] concluded that despite intense voluntary activation, the propagation of the action potential across the motor end-plate (from nerve terminal to muscle) remained unaffected. During voluntary activity, the only well described failures of transmission across the neuromuscular junction are seen during curarization and in the disease myasthenia gravis. In adult muscles, each skeletal muscle fibre receives innervation from only one a motor neuron, whereas each motor neuron makes contact with several muscle fibres. The mean number of muscle fibres per motor neuron (the ‘innervation ratio’) is about 10 for the small extraocular ª 2009 Adis Data Information BV. All rights reserved.
muscles, about 100 for intrinsic muscles of the hand, and up to about 2000 for large leg muscles like gastrocnemius.[73] The higher the innervation ratio, the greater the number of axonal branch points of a motor unit. The axonal branch points are thought to be particularly susceptible to propagation failure of the axonal action potential.[74,75] However, the role of axonal propagation failure in muscle fatigue is still unclear. 1.1.5 Differentiation of Muscle Fibre and Motor Unit Properties
Practically all muscles contain fibres and motor units of widely varying biochemical and physiological properties.[76,77] Physiological studies of motor units have shown that, within a single muscle, they typically vary greatly in their contractile speed, maximum force and resistance to fatigue. Furthermore, these various properties are co-varying, such that the slowest units tend to be fatigue resistant (type I fibres) and weak and the strongest ones are fast but relatively sensitive to fatigue (type II fibres). The differences in fatigue resistance are partly associated with differences in the ‘vulnerability’ of the EC-coupling. The biochemical properties of the myofilament ATPase activity are different between type I and II fibres. Several myosin subtypes can be distinguished.[78] The head of the myosin filament shows ATPase activity during the cross-bridge cycle.[11] The different myosin subtypes show different rates of ATPase activity and biomechanical properties. The cross-bridge cycle rate is slower in type I than type II fibres and therefore the ATPase turnover is lower in type I fibres. The cross-bridge cycle rates can differ up to 30 times between the different subtypes of type I and II fibres.[21] The consequence of these different subtypes of myofilaments is that one muscle can contain many subtypes of muscle fibres. Furthermore, fatigue-resistant fibres tend to have a higher activity of enzymes engaged in oxidative metabolism than the more fatigue-sensitive fibres. Isometric force generation of type II fibres decreases more than type I fibres during Pi accumulation at 30 mmol/L.[21,23] This effect is more evident at low temperatures.[79] In contrast, contraction speed of type I fibres is more susceptible Sports Med 2009; 39 (5)
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to Pi accumulation than type II fibres.[80] These effects are also more pronounced at low temperatures.[81] One should realise that the temperature of human skeletal muscle in vivo is about 32C at rest conditions and can rise to >39C during exercise.[82] Therefore, the effects of Pi accumulation on the biomechanical properties of myofilaments may be more pronounced in the in vitro experiments at low temperatures than during in vivo circumstances of exercise. The distribution of the different fibre types varies greatly between different muscles and across homologous muscles in different animal species.[83] Type I fibres tend to be relatively more frequent in muscles with a crucial role in posture (e.g. in antigravity muscles needed for standing). Compared with commonly studied laboratory animals (mice, rats, cats), human muscles have a very high percentage of type I fibres; in many human muscles, type I fibres (‘slow’) constitute about 50% of all fibres.[84] The firing frequency of the motor neuron declines during sustained isometric contractions.[85,86] The reason for this firing frequency decline is most likely an afferent feedback loop.[87] Fuglevand and Keen[88] have shown that a decrease in motor unit discharge rate may contribute to a decrease in muscular output during sustained isometric contractions. As mentioned above, the speed of the cross-bridge interaction of the muscle cell decreases due to accumulation of intracellular ADP (see figure 1).[19,20] This means that the firing frequency can slow down to maintain a fully fused muscle cell contraction. The reduction of the motor neuron firing frequency in combination with the decreased speed of the cross-bridge interaction enables the contracting muscle cell to maintain its mechanical output at a lower cost of energy. Some researchers hypothesize that a special mechanism exists for the optimal motor neuron firing frequency according to the change in biomechanical properties in the muscle fibres during sustained isometric contractions.[2,86] This phenomenon is known as ‘muscle wisdom’. Others debate this theory,[89] because the muscle relaxation after isometric contraction has not been thoroughly investigated yet. They argue ª 2009 Adis Data Information BV. All rights reserved.
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that, in order to study muscle wisdom properly, patients suffering from muscle disease with abnormal slow relaxation time, as in myotonia (affected sarcolemma) or Brody’s disease (affected sarcoplasmatic reticulum), should be investigated. 1.2 Effects of Exercise on the Internal Environment
In sudden muscle activation, the change from rest to intense activity is too rapid for an immediate external supply of the required energy substrates, so internal energy stores are used. The energy for muscle contraction has to be supplied as ATP. At very short notice, ATP can be generated from internal stores of creatine phosphate. Furthermore, ATP can be generated relatively rapidly by anaerobic glycolysis, using intracellular stores of glycogen as fuel and producing lactic acid as one of the metabolites. Only after some time can the increased metabolic requirements of an activated muscle be balanced, partly or completely, by increasing the level of functioning of the cardiovascular and respiratory systems. More oxygen and fuel (glucose, fatty acids) need to be supplied and more CO2 and other waste products (e.g. lactic acid) need to be removed. The intensity of the workload, the amount of muscle tissue involved and the type and duration of exercise all influence the impact of the active muscles on the internal environment. After the sudden onset of a steady level of exercise, it typically takes several minutes before heart rate and oxygen uptake have reached a new, higher, steady state. Under anaerobic conditions, the breakdown of glucose (glycogen) generates lactic acid as one of the end-products. Under aerobic conditions, lactic acid can be further processed, generating more ATP, CO2 and water. The performance of a matching rate of aerobic glycolysis becomes increasingly difficult at increasingly higher general workloads. The increase of lactate concentration in blood and extracellular fluids shows a marked acceleration above a certain workload, i.e. the ‘lactate threshold’ or OBLA (see also later, figure 4). The lactate threshold can be defined as the workload at which tissue Sports Med 2009; 39 (5)
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lactate production is exactly in equilibrium with the tissue lactate consumption. Above this workload the blood lactate concentration starts to increase.[90] Others define the lactate threshold as the workload at which blood lactate concentration exceeds 1 mmol/L above baseline.[26,91] OBLA is defined as the workload at which the blood lactate concentration exceeds 4 mmol/L.[92] An increased concentration of acid means an increased concentration of hydrogen ions, i.e. a lowering of pH. This increased proton load is partly buffered according to the reaction: Hþ þ HCO 3 $ H2 CO3 $ H2 O þ CO2 This reaction is associated with the generation of extra CO2, which is exhaled. As a result, there will be an increase in the respiratory quotient during the last stages of heavy exercise. For . untrained subjects this occurs at about 50–60% VO2max . , and for trained subjects at about 70–80% VO2max (figure 4).[26,27] In muscle tissue, the metabolism of the anaerobic glycolysis and purine nucleotide breakdown are linked to each other.[93,94] Ammonia emerges as adenosine 5’-monophosphate and is broken down to inosine monophosphate. Lactate is the end-product of the anaerobic glycolysis. As a consequence, the blood concentrations of both ammonia and lactate will increase during graded exercise. It is well known that workloads above the OBLA can be maintained for only a limited period of time before subjects get seriously fatigued and are forced to stop their exercise due to exhaustion (figure 4).[25-27] Hence, exerciseassociated fatigue sensations tend to increase in parallel with the accumulation of exerciseassociated metabolites (e.g. lactate). It is still unknown to what extent this parallel accumulation reflects a direct causal relationship. During graded exercise, only about 20–25% of all the consumed metabolic energy is converted into mechanical work, while the rest emerges as heat.[5,95] Thus, exercise causes a ‘heat load’ in the internal environment (see also section 1.3.4). ª 2009 Adis Data Information BV. All rights reserved.
Summarizing, the large number of effects of muscle exercise on the internal environment include: 1. An increased consumption and potential lack of oxygen and nutrients (glycogen, glucose, fatty acids); 2. An increased production and potential accumulation of CO2, hydrogen ions (‘proton loading’), lactate and ammonia; 3. An increased production and accumulation of heat (‘heat loading’). The larger the workload, the larger the effects of these variables are on the internal environment. It is conceivable that such changes in the internal environment might affect the functioning of the CNS, directly by interoceptive afferents and indirectly to a deterioration of the performance of the exercise-associated muscles. Visceral afferents from some cranial nerves project to the solitary nucleus of the brain stem.[96] To maintain the steady-state of the internal environment, the brainstem and hypothalamus are crucial.[97] A deterioration of the steady-state of the internal environment by exercise can induce inconvenient sensations of fatigue and of exhaustion. These inconvenient sensations have a devastating effect on exercise performance.
1.3 Effects of Exercise on the CNS
The function of the CNS is complex. The CNS plays a crucial role in the maintenance of the steady state of the internal environment. The motor cortex of the brain is responsible for the generation of the motor drive during exercise. We are conscious of this motor drive, but we are unaware of the concomitant motor control of muscles regulating our posture during exercise. Furthermore, the brain is the centre of our cognition. Despite the complexity of all these functions, our mind can concentrate on only one issue at a time; this issue is the object of our consciousness. In fact, we have a very limited state of consciousness. Gradually we become aware of sensations of fatigue and exhaustion during exercise. From a physiological point of view the awareness of these sensations has a warning role. Sports Med 2009; 39 (5)
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Besides these sensations of fatigue, neurophysiological changes also occur in the CNS during exercise. 1.3.1 Afferents and Motor Control
The CNS controls motor behaviour using sensory signals of many modalities. In humans, vision is very important for motor control,[98] and skin sensitivity is essential for the guidance of movements in direct contact with the external world (e.g. for manipulating objects). In all movements, the many afferents coming from the muscles themselves also play an important role. Muscle afferents have widely varying diameters and their functions are related to axonal size and, therefore, to conduction speed. All muscle afferents are connected to multiple different parts of the CNS, and their signals can be used in a multitude of ways. However, in all muscle contractions the muscle spindle afferents play a role because the afferents have a direct connection to motor neurons, producing monosynaptic excitation. Activity of muscle spindle afferents is caused by activity in gamma motor neurons. Thus, in voluntary muscle activation, a (minor) part of the total excitatory input to the motor neurons arrives via the reflex circuit of the ‘gamma loop’: gamma motor neurons/muscle spindles/a motor neurons. The role of muscle afferent feedback mechanisms in exercise and fatigue has been the subject of various recent investigations.[99-101] During sustained isometric contractions at maximum voluntary contraction (MVC) the EMG and the contraction force decrease synchronously. Bigland-Ritchie et al.[102] registered the firing rate of single motor units of the biceps brachii muscle during MVC by micro-electrodes under normal and ischaemic circumstances. During MVC, firing rates declined and recovered within 3 minutes after contraction. The recovery of the firing rate was absent if ischaemia was applied. The motor neurons are positioned in the spinal cord and show a decrease in the firing rate. These experiments suggest an afferent feedback loop between the muscle and its motor neuron in the spinal cord. It is hypothesized that the small chemo- and nociceptive muscle afferents (thin myelinated ª 2009 Adis Data Information BV. All rights reserved.
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[III] or unmyelinated [IV or C] fibres) are responsible for this feedback loop.[99,103] Martin et al.[103] evoked the biceps and triceps brachii muscles, the elbow flexor and its extensor, at two different levels in the neuromuscular tract by electrical stimuli. The corticospinal and reticulospinal tracts were stimulated via the mastoid processes at the cervicomedullary level. The response to this stimulus was an evoked twitch contraction of both muscles, which are each other’s antagonists. These experiments were applied with and without muscle ischaemia produced with an inflated cuff. The results of this study suggest that there is a feedback loop of III and IV nerve fibres in the extensor muscles. A response to this stimulus of fatigue in the extensor muscle was found. Surprisingly, the feedback loop of the extensor muscle also facilitates the contraction properties of the flexor antagonist. The feedback loop of the III and IV nerve fibres of the flexor muscles showed a response in the extensor antagonist, but no response in the flexor itself. It is hypothesized that the afferents that were triggered in the experiments of Martin et al.[103] and Bigland-Ritchie et al.[102] are type III and IV nerve fibres. Bigland-Ritchie et al.[102] measured the rate frequency of the single motor units, and Martin et al.[103] tested the excitability of the corticospinal tract. These observations suggest two different feedback systems. Recent research of Martin et al.[104] showed that stimulating type III and IV nerve fibres by saline infusions (triggering pain sensations by these nerves) reduced the motor-evoked potential (MEP) response to electromagnetic motor cortex stimulation (for an explanation of MEPs see section 1.3.3.[106,110]). The corticospinal tract has no presynaptic inhibition.[105] This suggests that the corticospinal tract is inhibited at the cortical level by the type III and IV nerve fibres. In summary, muscle afferents of type III and IV nerves have three effects: a decrease of the firing frequency of the motor neuron;[102] an inhibition or facilitation of the motor neuron;[103] an inhibition of the motor cortex neuron.[104] Sports Med 2009; 39 (5)
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1.3.2 Central and Peripheral Fatigue
Two types of fatigue can be distinguished: central versus peripheral fatigue. In peripheral fatigue, the origin of fatigue is outside the CNS. In all other cases the fatigue is generated somewhere in the CNS. However, these terms can be defined more precisely. Peripheral fatigue is defined as the loss of contraction force or power caused by processes distal to the neuromuscular junction, and central fatigue is a similar loss proximal to the neuromuscular junction.[106,107] During muscle exercise, an increased sense of effort probably means that, for some reason, the exercise or contraction can only be continued at the expense of an increased intensity of cortical commands. The reasons for such changed command requirements are often peripheral (drop of force-producing capability in muscles) but may also be situated within the CNS (e.g. changes in neuronal and/or synaptic properties). The degree of fatigue in the muscles themselves may be estimated using, for instance, electrical stimulation for assessing whether their maximum force has decreased. Under some experimental conditions, the component of ‘central fatigue’ can be estimated by comparing the maximum force obtained voluntarily versus the force resulting from maximum voluntary plus electrical stimulation (e.g. the ‘twitch interpolation technique’).[108,109] The superimposed electrical stimulation adds more force at high than at low levels of central fatigue. In ‘the superimposed electrical stimulation or twitch interpolation technique’ the muscles are activated by applied electrodes. These electrodes are attached at the skin surface. During sustained isometric contractions the muscles are activated electrically. This activation creates a superimposed contraction. By means of this technique one can distinguish between fatigue components in the contracting muscle (peripheral fatigue) and components within the CNS (central fatigue). In addition to central changes causing a less efficient central drive of the motor neurons, prolonged and intense bouts of motor exercise may also cause qualitative changes in the CNS control of movement, e.g. loss of coordination and increased correction-errors. Such aspects of ª 2009 Adis Data Information BV. All rights reserved.
‘central control fatigue’ have been the subject of little experimental investigation to date. 1.3.3 The Motor Cortex
Large parts of the brain are involved in the production and control of motor behaviour. Many of the final commands seem to be channelled via the primary motor cortex, which is also one of the best known portions of the motor system (partly due to its accessibility for experimental investigation). In conscious and intact humans, strong magnetic pulses may be used for activating the motor cortex transcranially, causing contractions and EMG responses to be facilitated and/or occur in various muscles.[106] By using this technique one is able to investigate the corticospinal tract by triggering the motor cortex and measuring the EMG signal and the produced mechanical output. The transcranial induced electromagnetic pulse evokes an activation of the neurons of the motor cortex. Via their action potentials these cortical neurons activate the motor neurons in the spinal cord. The final effect is a twitch contraction of the motor units of these motor neurons. These twitch contractions, the MEPs, can be recorded by the EMG. There is some delay between the transcranial magnetic pulse and the MEP due to the propagation time of the afferent signal from motor cortex to muscle fibre.[110] Applying such techniques, it has been shown that the excitability of the motor cortex changes during a fatiguing muscle contraction. After transcranial stimulation of the motor cortex during voluntary isometric contractions, the return of the continuous EMG signal of the isometric voluntary contraction showed a delay of about 200 ms.[111] This delay lengthens during a sustained contraction of 2 minutes at MVC. These transcranial stimulating tests suggest a change in the neuronal activity of the motor cortex and are considered to be a sign of central fatigue. Various investigations of normal and diseased nervous systems have led to the conclusion that the ‘sense of effort’, as felt during muscle contractions and motor exercise, somehow reflects the intensity of ‘commands’ issued from the Sports Med 2009; 39 (5)
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motor cortex.[112] Thus, this sensed information concerns internal CNS processes, reported via ‘corollary discharges’, rather than messages received from the periphery via sensory afferents. It is still unknown in which cortical region the ‘sensing’ of effort exactly takes place. The ‘sense of effort’ should be distinguished from a perception of the force produced. Usually, the effort is more easily assessed than force. However, under some conditions, some subjects may distinguish between these two modalities.[113] 1.3.4 The Core Temperature
In order to maintain a steady body temperature, extra body heat has to be dissipated.[114,115] In the last years, researchers have shown a clear link between hyperthermia and motor drive. The CNS is vulnerable to hyperthermia. Special neurons in the pre-optic area of the hypothalamus are sensitive for temperature changes, and the hypothalamus plays an important role in core temperature regulation.[116] During exercise, the contracting muscles produce heat, which acts upon the core temperature. Gonzalez-Alonso et al.[117] measured a gradual increase of the core temperature up to 40C during prolonged exercise. If it exceeded 40C, the central drive of the subjects faded away and they were unable to maintain the workload. A similar observation was obtained by Nielsen et al.[118] They measured the EEG activity of seven endurance-trained subjects during a gradual increase of core temperature. The subjects stopped at an average core temperature of about 39.8C. Probably, a core temperature of about 40C is a critical temperature. Reaching this core temperature reduces the central motor drive. Most likely the brain temperature during these circumstances could be an important limiting factor.[119] Todd et al.[120] investigated the effect of increased core temperature at the isometric MVC and during transcranial magnetic stimulation tests of the motor cortex at MVC. The motor cortex excitability remained unchanged at increased core temperature, but the silent period in the EMG after the superimposed stimulus increased under these circumstances. Reza et al.[121] investigated the relationship between transª 2009 Adis Data Information BV. All rights reserved.
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cranial magnetic stimulation of the motor cortex during voluntary contraction at different forces and its evoked silent period at the cortex using EMG recording. This silent period increased when the applied voluntary contraction force or torque decreased. These observations of Todd et al. and Reza et al. suggest that the increased core temperature induces an unknown inhibiting mechanism at the motor cortex. It is supposed that the thermoregulatory centres of the hypothalamus play a central role in this process.[120] The level of inhibition could be acting directly on the motor cortex or acting at a level before the motor cortex. NO-synthetase blockers were administered in the lateral ventricle of the brain in rats.[122] The exercise performance of these rats on rodent treadmills was reduced and they demonstrated a faster increase of body temperature compared with controls. After the exercise, the heat dissipation of the treated rats was reduced. The same researchers discovered that cerebral NO-synthetase blocking causes a decrease in the mechanical efficiency during rodent treadmill exercise in rats.[123] The cost of energy during exercise is therefore increased under these circumstances. Cheung and Sleivert[124] describe two models showing how exercise-induced hyperthermia might affect the motor drive of the CNS during exercise. One model states that during exercise the progressive heat loading is stressing the cardiovascular system, which in turn could limit the blood flow to the brain. Besides providing nutrition, the brain blood flow also drains heat. Therefore, a reduced brain blood flow is accompanied by a reduced brain heat loss. The other model suggests that the increased brain temperature may introduce the sensations of fatigue and the sense of effort during exercise directly. 1.3.5 Branched Chain Amino Acids and the Serotoninergic System
Skeletal muscle tissue consumes branchedchain amino acids (BCAAs; i.e. leucine, isoleucine, valine). This consumption of BCAAs is increased during exercise, i.e. the BCAA concentration in blood will then tend to decrease. BCAAs enter the brain using the same carrier Sports Med 2009; 39 (5)
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as tryptophan. Thus, if BCAA concentration goes down without a corresponding change in tryptophan level, more tryptophan will enter the brain. Tryptophan is the precursor of serotonin (5-hydroxytryptamine; 5-HT), an important transmitter substance in the brain. Prolonged exercise has two effects. Firstly, the concentration of BCAAs decreases, thereby altering the ratio of tryptophan-BCAA entering the brain in favour of tryptophan. Secondly, prolonged exercise leads to increased levels of fatty acids in the blood (see figure 2). The increase in free fatty acids causes an increase in the ratio of free versus bound plasma tryptophan, which in turn causes a further increase in the amount of tryptophan entering the brain. The increased levels of brain tryptophan lead to an increase in the effects of serotoninergic transmission. The final net effect seems to be an increased level of tiredness, such as the level that is associated with going to sleep.[125] Inspired by these findings, some athletes try to counteract sensations of fatigue by consuming BCAA-containing drinks during prolonged exercise. Blomstrand et al.[126] found a decreased tryptophan uptake by the brain during a prolonged exercise of 180 minutes with carbohydrate supplementation. However, oral supplementation of BCAA or omega-3 fatty Blood compartment
Brain tissue
1 Free-Trp or * BCAA
Trp
2
5-HTP
3
5-HT
BCAA Albumin
-FA
Albumin
-Trp
Free-FA * BBB Fig. 2. Tryptophan brain uptake and synthesis of serotonin (5hydroxytryptamine; 5HT) during prolonged exercise. 1 = the blood-brain barrier transporter; 2 = tryptophan hydroxylase; 3 = 5-hydroxy tryptophan decarboxylase; BBB = the blood-brain barrier; BCAA = branched chain amino acid; FA = fatty acid; 5-HTP = 5-hydroxytryptophan; Trp = tryptophan. The vertical arrows indicate the increase or decrease of concentration, and the arrows with an asterisk (*) are the effects introduced by the prolonged exercise.
ª 2009 Adis Data Information BV. All rights reserved.
acids had no effect on the endurance time of the exercise.[127] The results of Blomstrand et al.[126] suggest a decrease in tryptophan uptake by brain tissue during exercise with carbohydrate supplementation. However, investigations by Cheuvront et al.[127] raise some doubts about the effectiveness of this carbohydrate supplementation. 1.3.6 The Role of Cytokines
In the last decade the release of cytokines has been the focus of scientific interest. Fatigue is one of the major complaints in medical practice and is usually one of the symptoms of disease. In most cases the immune system is activated during illness. This activated immune system reacts in a cascade of response reactions. Cytokines play an important role in these response reactions. There is an increase in several types of cytokines during illness. The ‘sensation of fatigue’ during illness induces indolent and sluggish behaviour, an adaptive response to minimize metabolism. A reduced metabolism consumes less energy, saving the energy stock. It is hypothesized that cytokines induce this adaptive behaviour. Skeletal muscle exercise is accompanied by increased production of several cytokines. It is hypothesized that the same kind of cytokines that acts at the onset of illness introduces sensations of fatigue during and after exercise.[128,134] Cytokines form a heterogeneous group of small intercellular signalling proteins. They are produced de novo and secreted by many different cells. The same cytokine can be produced by different types of cells. The production of cytokines is induced by specific stimuli, such as an infection, physical and chemical stress, or traumatic events. The release of some cytokines can also trigger the release of other cytokines. Therefore, the kinematics of cytokine release is rather complex. Cytokines act on their target cells by binding at a special membrane receptor. After binding, the receptor is selectively stimulated by the cytokine and induces gene expression in these target cells via a second messenger. The final effects of the cytokine depend on the properties of its target cells. Sports Med 2009; 39 (5)
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+
?
IL-1 release TNF release
Effects of cytokines at the CNS
Strenuous exercise with muscle damage
IL-6
+
Sensation of fatigue
+ + ⎧ IL-6 ⎨ IL-1 ⎩ TNF +
IL-6 release
Plasma concentration
Exercising muscle
IL-6 ⎧⎨ IL-1 ⎩
+
IL-6 ⎧ ⎨ IL-1 ⎩
+
IL-6 ⎧ IL-1 ⎨ TNF⎩
+
Sensation of sleep
Sensation of illness
Pyrogenic response
Fig. 3. Overview of the interaction between exercise and cytokines. During exercise muscle cells start to release an increasing amount of interleukin (IL)-6. During strenuous exercise, messenger RNA (mRNA) of IL-1 and tumour necrosis factor (TNF) is synthesized in the mechanically stressed muscle cells. It is likely that the transcription of these mRNAs is the source of elevated plasma concentrations of IL-1 and TNF. + indicates that the ‘exercising’ muscles release IL-6 and that the cytokines IL-6, IL-1 and TNF induce the described effects in the CNS; ? indicates that exercising muscles during strenuous exercise might release IL-1 and TNF; › indicates increased.
Physical exercise is accompanied by increased blood plasma concentrations of interleukin-6 (IL-6).[128-131] It has been demonstrated that contracting muscles themselves are the source of the IL-6 that is produced during exercise.[131-133] The increase in IL-6 caused by physical exercise can be up to 50 times the baseline values during rest conditions.[134] Most likely, the recurrent calcium influx from the sarcoplasmatic reticulum to the sarcoplasm during muscle contraction is a major factor inducing IL-6 release from the muscles.[135] It is well known that strenuous muscle exercise, particularly eccentric exercise, is accompanied by muscle fibre damage introducing an inflammatory process post-exercise.[136] IL-6 is defined as a ‘myokine’, a cytokine that is released by exercising muscles.[137] The final effect of the exercise-induced IL-6 release and perhaps of the inflammatory reaction of the ‘post-exercising’ muscle is an increase in many different cytokines[134,138] including IL-1 and tumour necrosis factor (TNF). The increase in IL-1 and TNF is probably induced by strenuous exercise.[139,140] This hypothetical mechanism is shown in figure 3. After intense endurance workloads of 2.5 hours’ cycling[141] or 3 hours’ ª 2009 Adis Data Information BV. All rights reserved.
running,[142] the amount of muscle cell messenger RNA (mRNA) for TNF and IL-1 was elevated. So probably, besides IL-6, the cytokines IL-1 and TNF are also produced by the active muscle cells. It is not known to what extent the myofibrillar damage caused by the mechanical stress of muscle cell contraction induces this synthesis of mRNA for IL-1 and TNF.[141,142] The CNS is sensitive for some cytokines: IL-1 and IL-6 promote sleep,[143] and TNF, IL-6 and IL-1 have pyrogenic capabilities.[144] Administration of IL-6 in athletes introduced an increased sensation of fatigue and a reduced exercise performance.[145] Furthermore, IL-1 introduces sickness behaviour in animals.[146] The intensity of the sensations of illness in patients correlates with the levels of IL-1 and IL-6 spontaneously released from peripheral blood mononuclear cell cultures of these patients. There was no correlation between the sensations of illness and the plasma levels of IL-1 and IL-6.[147] These observations in animals and humans suggest that IL-1 and IL-6, among other factors, might introduce sensations of fatigue. Both interleukins are still increased post-exercise, thereby introducing exercise-avoiding behaviour because of Sports Med 2009; 39 (5)
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Oxygen uptake
a Oxygen uptake Supramaximal exercise
1.3.7 Brain Metabolism during Exercise
. VO2 max 50%
100%
Workload
b Blood lactate concentration (mmol/L)
fatigue, which lasts for some period of time. It is not known whether the sense of effort (see section 2.1) is affected by these interleukins.
Blood lactate concentration
OBLA . VO2 max
4 1 = *[ 50% Aerobic exercise
100%
Workload
Anaerobic exercise
Endurance time (min)
c 80 70 60 50 40 30 20 10 0
R2 = 0.80
50
55 60 65 70 75 80 85 90 . Individual LT as % of the VO2 max
Fig. 4. Terminology used in exercise physiology and its physicophysiological meaning. (a) Relationship between workload . and oxygen uptake. Workloads above maximal oxygen uptake (VO2max) are ‘supramaximal workloads’. At these supramaximal workloads, most of the power is produced by type II muscle fibres, which generate their intracellular adenosine triphosphate (ATP; necessary for the cross-bridge interaction), by the glycolytic pathway and breakdown of creatine phosphate. (b) Relationship between workload and blood lactate concentration. The different definitions for the lactate threshold (LT; exceeding 1 mmol/L increase of the baseline) and the onset of blood lactate accumulation (OBLA; 4 mmol/L) are shown. In this graph, aerobic exercise is defined as the workload until the lactate threshold or OBLA has been reached. The anaerobic threshold is the workload beyond lactate threshold and OBLA. During aerobic exercise, muscle power is produced predominantly by type I muscle fibres, which generate most of their ATP via . the aerobic pathway. The aerobic exercise ends at .about 50% VO2max in untrained subjects and at more than 80% VO2max in very well trained subjects. (c) Relationship between LT and endurance time. The LT was defined as the workload at which the blood lactate concentration exceeded the 1 mmol/L of baseline. The endurance time was estimated . during a workload at 88% VO2max in 14 volunteers (data obtained from Coyle et al.[91]).
ª 2009 Adis Data Information BV. All rights reserved.
Cerebral blood flow is impaired during exercise.[148,149] This has been demonstrated by different techniques. Herholz et al.[148] used 133Xe and Ide et al.[149] used near-infrared spectroscopy. Ultrasound Doppler methods showed an increase in blood velocity in the medial cerebral artery.[105,119,141,142,149-154] Nybo and Nielsen[154] demonstrated that this blood flow decreased during hyperthermia, suggesting an impaired cerebral blood flow. These results are contradicted by the findings of Madsen et al.,[155] who showed an increased blood velocity in the medial cerebral artery during dynamic exercise, but no increase in cerebral blood flow measured by 133 Xe. Most likely, these investigations reflect an enhanced brain tissue blood flow during exercise. Brain metabolism alters during exercise. Madsen et al.[155] did not find a clear increase in brain oxygen uptake during exercise at a workload of 50% of the maximum oxygen uptake. Compared with resting levels, Ide et al.[149] found a decreased difference between the oxygen content of arterial versus venous blood at a workload of 30% of the maximum oxygen uptake. However, at a workload of 60% of the maximum oxygen uptake, the decrease was reversed into an increase. The same observations were found by Dalsgaard et al.[150] If cerebral blood flow increases during exercise, these observations suggest that oxygen uptake by brain tissue is increased, especially during intensive workloads. In resting conditions, brain metabolism relies almost completely on the oxidation of glucose for its ATP production.[150] This means that the ratio of brain tissue oxygen uptake to brain glucose uptake is 6 : 1. During starvation, the oxidation of ketone bodies contributes to a considerable proportion (up to 25–50%) of brain metabolism.[156] The ratio of the cerebral oxygen/glucose uptake decreases during an exercise workload of 60% of the maximum oxygen uptake (Ide et al.[149]). However, this ratio first decreases during an exercise protocol with a graded workload till Sports Med 2009; 39 (5)
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exhaustion and then increases to resting levels in the last part of the exercise (Ide et al.[157]). In both experiments an uptake of blood lactate was measured in brain tissue. During exercise, brain tissue shows a disproportionately higher uptake from glucose and lactate than from oxygen. These observations suggest that exercise might have an anabolic effect on brain tissue. Kemppainen et al.[158] investigated brain metabolism during exercise with 18fluoro-deoxy-glucose positron emission tomography (PET). They investigated two groups of subjects, an exercise-trained group and a less trained group. The subjects exercised at three different workloads (30%, 55% and 75% of their maximum oxygen uptake) for 30 minutes. In general, glucose uptake in the brain decreased and showed a negative correlation with the obtained blood lactate concentration. Furthermore, the reduction in brain glucose uptake was more pronounced in the frontal brain areas. Even though there were no changes in the blood lactate concentration in both groups, the effect on brain glucose uptake reduction was more pronounced in the well trained group. It was hypothesized that the brain glucose uptake was reduced due to an increased brain lactate uptake with increasing exercise loads and that brain tissue used lactate in favour of glucose for its oxidative energy production. 2. Psychological Aspects of Exercise 2.1 Sensations Related to Exercise
The sensations of fatigue that develop during a sustained isometric contraction are different from the sensations of fatigue that develop during running a 42 km marathon. In both situations the sense of effort increases but the two types of exercise differ in the associated physiological effects and in the associated experienced sensations of fatigue. The sustained contraction leads to a marked accumulation of muscle metabolites. When running a marathon, there is a prominent depletion of the muscle glycogen stores. The day after prolonged isometric contraction one may not notice any lasting sensations associated with the exercise, while after a marathon one is likely ª 2009 Adis Data Information BV. All rights reserved.
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to experience tiredness for one or several days. Thus, an increase of sense of effort might be associated with different patterns of ‘fatigue’. As a psychological quantity, the ‘sense of effort’ reflects one’s exercise capacity. From the physiological point of view, the ‘sense of effort’ reflects more or less the quality of the motor drive from the cerebral cortex to the motor neurons of the spinal cord. It is supposed that the centrally generated motor commands create the sense of effort by a corticofugal feedback system.[2,112,159] In rats, collaterals of the corticospinal tract terminate at the striatum.[160-162] Therefore, the striatum receives an exact copy of the motor cortex output to the spinal cord. Exercise might change the steady state of the internal environment. Interoceptive afferents send back the actual physiological status of the internal environment to the CNS. It is not known which neuro-anatomical structures in the CNS generate the sense of effort and the sensation of fatigue. A synopsis of possibilities is shown by St Clair Gibson et al.,[163] who suggest that ‘the sensation of fatigue’ is the conscious awareness of changes in subconscious homeostatic control systems. During exercise this means a gradual shift from a subconscious to a conscious awareness. The homeostatic control systems of the CNS are situated in the nuclei of the brainstem and hypothalamus. These nuclei integrate the physiological changes of the internal environment and most likely modulate the higher centres of the brain. Finally, the highest centres of the brain are reached by creating an awareness of sensation of fatigue and sensation of exhaustion. The PET images from Laureys et al.[164] of the brains of people in four different states of consciousness are interesting, but also very sad. These different states were healthy people, patients with a ‘locked in syndrome’, patients with a ‘minimal consciousness state’ and patients with a ‘vegetative state’. In these subsequent PET images the brain tissue glucose uptake decreased, especially in the medial posterior cortex (the precuneus or lobus quadratus). The glucose uptake by the precuneal cortex in the vegetative patient was hardly measurable. These authors[164] hypothesized that this mid-brain area, which is Sports Med 2009; 39 (5)
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situated posterior of the sulcus centralis, plays an important role in the state of consciousness. It is well known that the sensory input to the brain cortex is projected to and processed by the cerebral cortex posterior to the sulcus centralis. Based on the observations of Laureys et al.[164] and Cavanna and Trimble,[165] it is conceivable that the precuneus plays an important role ‘‘in the creation of awareness.’’ Perhaps, this part of the brain cortex also plays an important role in the creation of the ‘awareness of the sensation of fatigue’ or ‘awareness of the sense of effort’ during exercise. The sense of effort can also be affected by a decrease in the motor output because of physiological changes within the muscle itself. The pool of recruited motor units has to be extended in order to maintain the same motor output under these circumstances. This produces an increase of the pool or a change in firing frequency of active neurons of the motor cortex, which in turn may create an increase in the sense of effort. In this case one might also experience sensations of fatigue. However, this form of fatigue is not produced by changes in homeostatic control systems of the CNS, but by changes within the muscle itself. 2.2 Rating Points of Exertion (Borg Scale)
In the beginning of the sixties, Borg developed a psychophysical scale (Borg scale) that linked the experienced sensations of exertion to the performed exercise intensity.[4,166] These scales contain two variables, a ‘physical component’ and the ‘perceived magnitude’. The latter is a psychological component and it represents the intensity of the perceived sensations during the exercise performance. The psychophysical scale represents the relationship between these two variables.[167] Two parameters estimate the physical properties of exercise, the type of exercise performed and the endurance time. In dynamic exercise there is a linear relationship between . workload,[11,27,119] represented as VO2max, and heart rate (see figure 4). Other parameters can also be used, such as the percentage of MVC during isometric contractions.[168,169] Therefore, exercise workload can be represented by one of these parameters. The Borg scale contains 15 ª 2009 Adis Data Information BV. All rights reserved.
rating points of exertion (RPE). As a physical parameter, Borg used the heart rate during exercise.[4] There is a high correlation between these two parameters.[166,170] It is hypothesized that cardiopulmonary, metabolic and other local afferents within the body cause the changes in perceived exertion during exercise. However, it is not clear how the CNS integrates these signals to the overall sense of exercise exertion. The afferent input to the heart muscle was manipulated in volunteers by using atropine and b-receptor blockers.[171,172] Atropine inhibits its parasympathetic innervation by blocking the acetylcholine receptor, b-receptor blockers inhibit its sympathetic innervation. Eklblom and Goldbarg found a nonsignificant increase of RPE after administration of nonselective b-adrenoceptor blockers (b-blockers) and atropine.[172] A similar effect of nonselective b-blockers on RPE was also found by others.[173,174] The effects of the selective b1-blockers are less pronounced than the those of the nonselective agents.[173] The observations during prolonged exercise on cycle ergometers of RPE during differences in cadence of cycling are interesting. At a cycling rate of 40 rpm the RPE was higher than at 60 or 80 rpm.[175] These observations correspond to the observations of the optimal pedalling rate of about 90 rpm during competitive cycling.[176] Baron[177] found an optimal power output at about 100 rpm. These observations suggest that the RPE represents the essential sensitive information. This sensitive information enables the CNS to estimate the optimal power output during exercise. 2.3 The Teleoanticipatory System and Other Concepts 2.3.1 The Teleoanticipatory System
Ulmer[178] created the concept that a control system should exist which estimates the optimal power output to perform the goal of the exercise. This system contains a ‘finishing point or the goal of the performed exercise’ and a ‘programme’. This ‘programme’ is able to ‘estimate’ the optimal power output to reach the ‘goal of the performed exercise’. Ulmer[178] describes this system as a Sports Med 2009; 39 (5)
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‘teleoanticipatory system’ (teleos = final or last). This system could be compared with one of the important tasks of former flight engineers in aviation. The flight engineers calculated before a flight how much fuel an aeroplane should use to reach the destination at an optimal flying speed. Saving fuel is an important cost-reducing factor for aviation companies. During the flight the engineers measured fuel consumption continuously and recalculated how the destination of the flight could be achieved optimally. Ulmer[178] suggests that a similar system should also exist in the execution of human exercise. This ‘teleoanticipatory system’ contains a feed-forward component, which estimates the metabolic rate of exercise per time unit. A feedback control loop compares the actual metabolic rate with the estimated metabolic rate. For ‘‘a precise feed-forward calculation’’ it is necessary to have ‘‘a template which contains existing data of exercise performance.’’ If this ‘teleoanticipatory system’ exists in humans, it is interesting to contemplate whether this template is acquired by previous exercises (training) or whether this template is inborn. An essential parameter for the functioning of this system is the ‘measurement of the energy turnover during the exercise’. It has been the scope of recent research to study how the CNS is able to estimate this turnover and how this ‘metabolic rate measurement’ is linked to the RPE.[170,178-180] 2.3.2 The Central Governor Model
Noakes[151-153] expects there must be a ‘central governor’ that matches ‘the sensatory information of exercise’ (feedback information) with ‘the aim of exercise’ (feed-forward information) – a system similar to Ulmer’s. As an example he uses the 42 km marathon. The marathon is an endurance race of a little more than 2 hours. Haile Gebrselassie ran the Berlin marathon of 2007 just within 2 hours and 5 minutes. According to Noakes, this is only possible if there is a match between ‘estimated workload’ and ‘performed workload’. There must be a centre in the body that obtains information on the maximum workload and maintains homeostatic control at the same moment. This concept is the ‘central governor model’ (CGM). Is the ‘capability of ª 2009 Adis Data Information BV. All rights reserved.
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feed-forward estimation or calculation’ one of the most important capabilities of the CNS in humans? Humans are able to give a preview and to work out a plan; we can act in this way because of the calculating capacity of our telencephalon. In other words the feed-forward capability in humans is well developed and has even reached abstract forms. So ‘human feed-forward calculation’ can be used during endurance exercise. This means that Noakes’ central governor could be identified as a function of the higher centres of the CNS. Noakes states that his CGM explains all forms of exhaustion during exercise, including those exercises with an intense workload.[153] 2.3.3 The Catastrophic Failure Model
The opposite of the CGM is the model of ‘catastrophic failure’.[151,153] In this model, exercise stops if one or more of the bodily systems are stressed beyond their capacity. For example, the limited oxygen and nutrition supply to exercising muscles leads to local intramuscular hypoxia and anaerobiosis, which is the cause of exhaustion. Weir et al.[181] debate Noakes’ statement that the CGM explains all forms of exhaustion during exercise. They discuss the effect of accumulation of metabolites at exercise of full power output. For example, the decline in running speed during a 400 m athletics race is used as an argument. During every 100 m the average speed of the athletes declines by about 0.5 m/s (1.8 km/h). Therefore, the speed has reduced by about 7 km/h after 400 m. They wonder how far athletes are using a pacing strategy during these 400 m races, and how far is this decline of speed due to processes within the exercising muscle itself? 2.3.4 Arguments against the Central Governor Model
The authors of this manuscript also have their doubt about Noakes’ concept of exercise-induced exhaustion in every form of exercise. First of all, a skeletal muscle is composed of different types of muscle fibres, ranging from fatigue-resistant (type I) to fast-fatiguable (type II) fibre types. Muscle fibres are recruited according to the size principle.[73] This means that at low exercise workloads, mainly type I fibres are recruited. If Sports Med 2009; 39 (5)
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the exercise workload gradually increases, type II muscle fibres are also recruited. The effect is an increase in performed workload. Type I fibres have a ‘dominant mitochondrial metabolism’,[182] suggesting that type I fibres are able to produce mechanical power when there is sufficient oxygen supply. Type II fibres have a higher glycolytic activity, indicating that type II fibres are able to produce power in the absence of sufficient oxygen supply. Therefore, sooner or later, lactate and proton accumulation will occur in these fibres. Proton accumulation causes a decrease in contraction force (see section 1.1.5). A second indication is the skeletal muscle metabolism during resting conditions. In muscles that contain mostly type I fibres, oxygen consumption is the highest and blood supply is the lowest. This suggests that the metabolism of muscles that contain mostly type II fibres relies on a higher amount of anaerobic metabolism that exists during resting conditions.[183,184] The third argument comes from vertebrate evolution. Vertebrates and cephalochordates belong to the phylum of the chordata and have the same ancestor. The amphioxus, also called a lancelet, belongs to the cephalochordata and this animal has no skeleton, but a notochord. The CNS of the amphioxus, a tube-like structure, is studied nowadays to understand the early development of the CNS of the vertebrates (see Butler and Hodos[185]). The myotomes of the amphioxus possess superficial and deep muscle fibres.[186] The deep muscle fibres have type II (white fibre) morphology and the superficial muscle fibres have type I (red fibre) morphology.[187] These deep white muscle fibres are used in escape behaviour from predators.[186] To escape from predators is an all-or-nothing situation. The superficial red muscle fibres are used during undulating swimming, when the animals have prolonged periods of swimming during vertical migration.[186] In the larvae of the amphioxus these two different muscle fibre types are linked to two different neuronal circuits.[188] Amphioxus shows escape behaviour after triggering skin surface mechanoreceptors.[186] Primitive lower vertebrates such as agnatha, teleost fishes and amphibians possess one pair of giant Mauthner ª 2009 Adis Data Information BV. All rights reserved.
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neurons. These two Mauthner neurons are bilaterally situated near the synapse of the vestibular branch of the VIII nerve in the medulla oblongata.[185] The axons of these two Mauthner cells give collateral branches to each segment of the spinal cord, which terminate at the motor neurons of the white muscle fibres. Furthermore, these collaterals also trigger the descending axons of higher centres of the CNS, which innervate the motor neurons in the spinal cord. The Mauthner cells get afferents from the lateral line system (mechanoreceptors), the vestibulocochlear nerve (N VIII) and perhaps the visual system.[185] In the amphioxus, the escape system is also triggered by one pair of giant cells, the large paired neuron number 3.[188] Amphioxus and vertebrates have a common extinct ancestor. How far are these neuromuscular systems of these lower vertebrates analogues or homologues of those neuromuscular systems of the amphioxus larvae? In amphioxus larvae and in lower vertebrates, escape behaviour is mediated by a special neuronal locomotor system, which triggers the fast-fatigable type II muscle fibres. Because of the special properties of the type II muscle fibres, an instant high mechanical output, the animals are able to escape from predators in life-and-death situations. Accumulation of metabolites inside the type II muscle fibres, which affect the fibre contraction properties, is the concomitant consequence of the high power output by the type II muscles during escape. Therefore, the high muscular power output of these type II muscle fibres can be produced for only a short time. Muscular fatigue will decrease the power output. However, these fibres recover after the lifesaving escape. If fatigue develops in the muscle fibres during escape, the destiny for the animal is to be eaten. To what extent can this escape be compared with the recruitment of type II muscle fibres during intense exercise? In higher vertebrates, including humans, the type I and II motor neurons of the spinal cord are to a large extent controlled by the neurons of the cerebral cortex via the corticospinal tract. So in higher vertebrates the dominant centres for motor control have shifted from hindbrain structures to forebrain structures. Humans are able to recruit the type I Sports Med 2009; 39 (5)
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and II motor neurons of the spinal cord gradually until MVC or intense workloads are reached during dynamic exercise (the size principle[73]). In fact, we are able to smoothly activate two evolutionary different muscle fibre systems. Despite this smooth gradual activation of the motor neurons, we notice to some extent how intensely and for how long we are able to sustain the produced power or contraction force. The higher the workload, the shorter the endurance time. If we choose exercise of high intensity, we accept that the endurance time is limited to a short period. In our opinion, it is better to distinguish between ‘muscle fibre type I and type II exercise’, which is based on the origin of the different tasks of motor output of the two muscle fibre types. The observation from one of the volunteers in our extremely exhausting treadmill experiments[40] (range of the endurance time was 30–160 seconds) is very interesting. During these intense exercises this volunteer said, ‘‘I wanted to maintain the running speed, but I noticed that my muscle power was fading away despite my motivated drive.’’ He also said that this fading away of muscle power was a very unpleasant sensation for him. This volunteer was a well trained endurance time cyclist. How far did he show ‘fibre type II exercise-avoiding behaviour’?
2.4 The Effect of the Intensity of the Workload
In the sixties, Rohmert[189] investigated the relationship between endurance time and isometric contraction. He found an inverse exponential relationship between applied isometric force and endurance time. One should realise that muscle blood flow is affected by contraction forces. An impaired blood flow reduces the endurance time of the contracting muscle. If skeletal muscle cells perform isometric contractions at high contraction forces, muscle blood perfusion is occluded by the high pressures inside the muscle compartment. Barcroft and Millen[190] found a complete occlusion of blood flow in calf muscles at 30% MVC. Lind et al.[191] demonstrated complete occlusion in the muscles of the forearm at 70% MVC. So, isometric contractions between ª 2009 Adis Data Information BV. All rights reserved.
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30% and 70% of MVC will lead to occlusion of muscle blood flow. In dynamic .exercise, endurance time is related is to a subject’s VO2max. The OBLA of a subject . somewhere between 50% and 80% of the VO2max (figure 4). The OBLA of top athletes performing endurance sports like cycling, running or .skating ranges between 70% and 80% of the VO2max. Exercises at workloads below OBLA can be maintained for very long times (figure 4), and they rely predominantly on the recruitment of type I muscle fibres. During these workloads, exhaustion is caused by emptying of the energy stock. The energy stock consists of glycogen stocks in muscle and liver tissue and of the stock formed by the fat tissue. Athletes need to eat and drink during the exercise in order to maintain their workload as long as possible. Cytokines probably play an important role in the release of glucose from intracellular glycogen and redistribution of glucose over the different types of cells. In isolated hepatocytes of rats it has been demonstrated that IL-6 reduces the intracellular glycogen stock.[192] One of the effects of IL-6 is the release of glucose by hepatocytes to maintain sufficient blood glucose concentrations during exercise.[193] Abdelmalki et al.[194] made some interesting observations. One hour prior to a prolonged treadmill run until exhaustion, rats received baclofen, a GABAB agonist. Control rats did not receive any drug. GABA is an inhibitory neurotransmitter. The endurance time of rats that had received baclofen was longer than the endurance time of control animals that had received placebo. The glycogen stock in liver and muscle tissue was more depleted in the baclofen-treated animals compared with the controls. It can therefore be concluded that baclofen boosts the glycogenolytic effect of IL-6 release of the exercising muscle. At workloads above OBLA, the steady state of the internal environment cannot be maintained, because type II muscle fibres are also recruited. Under these circumstances, the homeostasis of the internal environment is affected by accumulation of lactate, ammonia, acid (proton loading) and body heat. Sooner or later the athlete has to stop or reduce the workload. To estimate a subject’s OBLA, the blood lactate concentration is regularly Sports Med 2009; 39 (5)
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measured during a graded exercise with increasing workloads.[26,27] . It is possible to apply workloads above VO2max: the supramaximal workloads. Under these circumstances, a large part of the generated workload is produced by type II muscle fibres. . During exercise loads far beyond the VO2max, the steady state within the muscle cell is the bottle neck. When exposed to these supramaximal workloads, the muscle cell ATP production has to rely on its cellular energy stock, creatine phosphate and glycogen. Glycogen and/or glucose are broken down to lactate and creatine phosphate to creatine and inorganic phosphate. These metabolites accumulate within the muscle cell itself, affecting the steady state. Most likely the endangerment of the intracellular steady state causes the EMG frequency spectrum to change to lower frequencies.[39,40] 3. Disease and Fatigue during Exercise 3.1 Diseases in General 3.1.1 General Aspects of Disease
Fatigue is one of the most often reported complaints during illness, and usually also the first symptom. Of the total number of people who died in the Netherlands in 2006, about 30% of deaths were caused by malignancies, and about the same percentage were caused by cardiovascular diseases. Lung diseases caused 10% of the total deaths (source: Statistics Netherlands; see www.cbs.nl). It is not known whether the Dutch data are comparable to the data of other countries. These diseases usually involve a long time (months to years) of deteriorating illness, which can affect a patient’s exercise capacity tremendously. Especially in malignancies, the foremost complaints a long time before the disease is finally detected are often only malaise and fatigue, which affect the patient’s exercise performance. It is of medical interest to know how pathological processes inside the body generate these sensations of fatigue and malaise, but the current knowledge is only fragmentary. In many cardiovascular diseases, cardiac output is often reduced, which has a direct effect on exercise capacity. In lung diseases, oxygen uptake and ª 2009 Adis Data Information BV. All rights reserved.
Micro-organism infections Immune diseases
Tissue damage
Inflammation
Malignancy
Release of IL-1, IL-6 and TNF
Release of IL-6 and TNF
−
−
Brain
?
Lung − Cardiac pump function − Anaemia
−
Muscle −
Exercise
Fig. 5. Schematic view of how different kinds of diseases might influence exercise performance. Some links are not shown in this figure to keep this schematic view simple. Usually, malignancies induce inflammation reactions. Bone marrow malignancies can be accompanied by anaemia. Lung diseases such as chronic obstructive pulmonary disease are often accompanied with chronic inflammation. These links between the different diseases are not shown, but they enhance the symptoms of exercise-induced fatigue and malaise. IL = interleukin; TNF = tumour necrosis factor; - indicates the inhibiting effect on brain and muscle performance of the different cytokines and organ systems.
carbon dioxide output might be reduced. Diseases of the intestines affect the steady state of the internal environment, causing onset of fatigue symptoms at an earlier stage of exercise and a more prolonged recovery after exercise. In many illnesses more than one organ is affected. For example, malignancies, especially of bone marrow origin, are often accompanied by anaemia. Therefore, fatigue and exercise performance can be harmed by several mechanisms. Figure 5 shows how these different mechanisms can influence exercise performance. 3.1.2 Cytokines and Illness
Sick individuals experience malaise accompanied by fatigue and disinterest for daily activities. Animals also show ‘sickness behaviour’. One of the important effects of sickness behaviour is a reduction in daily activities, which in turn lowers the daily energy expenditure. The ‘sickness Sports Med 2009; 39 (5)
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behaviour of humans and animals’ is an efficient strategy to reduce energy consumption during illness. The energy-saving strategy during such a period is to reduce muscular activity by a change in behaviour. In many diseases the immune system is activated. The reason for this activation is usually an infection by micro-organisms (viruses or/and bacteria) or tissue damage by trauma.[195] The penetration of micro-organisms into the internal environment causes cell and tissue damage, which in turn may activate the immune system. Macrophages and mast cells are the first cells of the immune system to be activated. Activated macrophages release, amongst other cytokines, IL-1, IL-6 and TNFa.[128,136,146,196,197] During illness, the same cytokines are released as those causing fatigue sensations during exercise. Cytokines and other substances activate leukocytes during inflammation. In one study, intraperitoneal administration of IL-1[198] in rats caused reduced social activities and feeding behaviour. Many researchers have observed a pyrogenic effect of IL-1 and IL-6, but most likely this was caused by the use of heterologous cytokines. Wang et al.[199] demonstrated that homologous IL-1 and IL-6 have no pyrogenic effect in animals when they are administered intraperitoneally. Recently, Blatteis[200] argued that cytokines possess no pyrogenic capacity themselves, but mediate the pyrogenic response. It is not known whether his observation regarding heterologous and homologous cytokines will affect the observations of many researchers in relation to sickness behaviour and other effects of cytokines. The current opinion is that the cytokines IL-1, IL-6 and TNFa play an important role in the pathogenesis of sensations of sickness and its accompanying behaviour in humans. During illness, humans show lethargic behaviour accompanied with sensations of fatigue and malaise (see figure 5). 3.1.3 Some Effects of Anti-Inflammatory Drugs
Autoimmune diseases often need prolonged medication. Usually the aim of the medication is to suppress the chronic inflammation, which can cause irreversible tissue damage. NSAIDs and ª 2009 Adis Data Information BV. All rights reserved.
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corticosteroids have a potent anti-inflammatory effect. Corticosteroids induce catabolism, which can induce loss of skeletal muscle mass. This loss of muscle mass directly reduces exercise capacity. In animal studies, subcutaneous injections with dexamethasone for 3 weeks caused a decrease in the diameter of type I and II muscle fibres. The contraction properties of the muscles of these animals were also investigated in vitro. The diaphragm muscles of the dexamethasone-treated animals were less fatigue resistant than those of controls.[201] To the best of our knowledge, there is only one report about the effect of corticosteroids on the composition of muscle fibre types in humans.[202] In this study, transplanted kidney patients were observed, where one group received prednisolone and the other group was treated with an IL-2 receptor inhibitor. A shift in the type I/type II muscle fibre ratio towards more type II fibres was found in the prednisolone-treated patients. Based on these observations, it can be concluded that corticosteroids, especially when used chronically, can induce muscle fibre atrophy. This will in turn cause a reduction in total muscle mass, which negatively affects muscle contraction properties. Contracting muscles adapt to the applied exercise workload by fibre proliferation after several weeks. This is a normal effect of training.[182,203] NSAIDs negatively affect these training effects in animals.[204] Therefore, care needs to be taken when using NSAIDs in sports injuries. Treatment of pain after sports injuries with NSAIDs relieves the pain in the first days, but can induce other sports injuries at a later time because of a decreased muscle fibre adaptation. Therefore, prolonged use of NSAIDs and corticosteroids during chronic illnesses induces muscle fibre atrophy and reduces muscle adaptations to exercise training. However, the first aim in these diseases is to reduce the intensity of the inflammation. Most likely this effect of reduced intensity in inflammation counterbalances its negative effect on the skeletal muscle properties, which overall might create better exercise performance and exercise-induced fatigue resistance. [See discussion between physicians (‘in vivo research’) and researchers (‘clinical experience’) in the Journal of Bone Joint and Surgery.[205]] Sports Med 2009; 39 (5)
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3.1.4 Vascular and Heart Diseases
One of the major effects of vascular and heart disease is a decrease in cardiac output and/or decrease in blood supply to organs and muscles. The amount of oxygen that can be transported per unit time from the lungs to the muscles depends on several factors. In healthy subjects these factors are the haemoglobin concentration and the cardiac output. In these healthy subjects . the maximum cardiac output determines the VO2max (see figure 4). Reduced cardiac output can have a dramatic effect on muscle oxygen uptake and muscle lactate formation. Usually during these . diseases a reduction of the VO2max is observed, which decreases one’s exercise capacity.[206-208] Wasserman[208] showed that the ratio of oxygen uptake/performed workload remained normal in coronary artery patients, despite the reduced oxygen uptake. This decrease in oxygen uptake may be caused by a decrease in cardiac output due to myocardial ischaemia. Occlusion of the main arteries supplying muscle tissue can reduce exercise performance. An example of this is intermittent claudication. The predominant cause of cardiac pump malfunction and vascular occlusion is the occurrence of lesions in the arterial wall by arteriosclerosis. These lesions finally narrow the lumen of the artery. Arteriosclerotic lesions show IL-6[209] and TNF gene expression.[210] In arteriosclerosis, IL-6 levels are increased.[211] Ridker et al.[211] showed that there was a positive correlation between a higher baseline IL-6 blood concentration and myocardial infarction. Therefore, besides the negative impact of reduced cardiac output due to the myocardial ischaemia, the increased levels of IL-6 and TNF produced by the arteriosclerotic plaques can also cause prodromal symptoms of exercise-induced fatigue and symptoms of malaise (see sections 1.3.6 and 3.1.2). It is not known how the decreased muscle blood supply changes the exercise-induced IL-6 release of the contracting muscles. Is the proportion of IL-6 release the same as in contracting muscles with sufficient blood supply or is this muscle IL-6 release enhanced by the reduced blood supply? In sports and rehabilitation, weight-lifting training programmes are used. The aim of these ª 2009 Adis Data Information BV. All rights reserved.
programmes is to improve total muscle mass and muscle strength.[182,203] Intense muscle contractions cause compression of the muscular vessels and capillaries. This vascular compression increases total peripheral resistance, creating an increase in arterial blood pressure.[212] An increase in arterial pressure elevates the systolic pressure in the left ventricle and increases the intramural pressure of the left ventricular wall during the systolic phase. The increase in intramural pressure reduces the coronary blood flow, but the higher arterial pressure during diastole increases this coronary flow.[213] It is not known whether increased systolic intramural pressure has an effect on myocardial perfusion during intense muscle contractions. How far do situations of intense isometric contraction force, like weightlifting, impede myocardial perfusion? This could be clarified through research, if technically possible. Dynamic exercise training increases muscle blood flow and induces blood volume workload for the heart muscle. Thus, isometric contractions cause pressure loading and dynamic exercises cause volume loading of the left ventricle. These two different haemodynamic effects of exercise need to be distinguished. 3.1.5 Malignancies
One of the first signs of malignancy is complaints of fatigue symptoms and complaints of malaise. Sometimes they are accompanied by a reduced capacity of exercise performance. Every physician becomes alert if a 50- to 60-year-old patient starts to show these symptoms. ‘‘Could these symptoms be caused by a malignancy?’’ is one of the thoughts in the physician’s mind. These prodromal complaints usually manifest months before the malignancy is finally diagnosed. What or which substances could cause these prodromal symptoms to occur? Every malignancy shows expansion of tumour mass and dissemination of its tumour cells. There are signs that an intact immune system is able to eliminate developing malignancies – an indication that there must be a system of immunosurveillance.[214,215] Thus there is an interaction between the immune system and the developing malignancy.[216] Sports Med 2009; 39 (5)
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Immunosuppressed transplant patients show a higher incidence of malignancies. In some cases of malignancy the immune system can promote tumour growth.[217] It has been demonstrated that TNF is capable of inducing a tumourpromoting inflammation in CT-26 colon cancer cells.[218,219] Therefore in some cases of malignancy these research observations suggest that the exercise-induced TNF release could stimulate tumour growth. In these circumstances the symptom of fatigue could have a protective role. Langowski et al.[220] discovered in several human tumours a significant RNA up regulation of IL-23. The same authors have demonstrated in mice that IL-12 might have a protective role in papillomas. Peake et al.[221] demonstrated an increase of IL-12 (subtype 40) after prolonged exercise (45–60 minutes) at moderate to intense workloads. Might exercise therefore play a protective role in some types of malignancy? Kim et al.[222] screened 242 colorectal adenoma cases and 631 controls for the prevalence of increased levels of IL-6 and TNFa. They found evidence of higher levels of IL-6 and TNFa in the patients with colorectal carcinoma. If we know that increased levels of IL-6 and TNF are linked with sensations of fatigue in humans and exerciseavoiding behaviour in animals (see section 1.3.6), this study suggests that the release of cytokines by malignant proliferation could play an important role in complaints of fatigue. In summary, it is hypothesized that exercise could have different effects in malignancy. It might protect via exercise-induced IL-12 release in some malignancies and it might enhance some tumour types by exercise-induced TNF release. Are the prodromal symptoms of fatigue and malaise at the onset of the malignancy caused by tumour-induced release by cytokines? IL-1, IL-6 and TNF are the first candidates for further research. 3.1.6 Pulmonary Diseases
Pulmonary diseases can have a tremendous effect on exercise capacity. The lungs are the organs that exchange oxygen and carbon dioxide with the environment. The gas exchange relies on three important factors: (i) the diffusion of oxygen and carbon dioxide via the alveolar-capillary ª 2009 Adis Data Information BV. All rights reserved.
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membrane; (ii) the alveolar blood supply; and (iii) the ventilation of the alveolar space. The amount of gases crossing the alveolar-capillary membrane by diffusion depends on the total surface area of alveolar-capillary membrane, the thickness of the membrane and the gas pressure difference on both sides of the membrane (Fick’s Law[224]). The intercostal muscles and the diaphragm are responsible for adequate ventilation of the alveoli. These ‘respiration’ muscles are especially active during inspiration. During inspiration the elastine fibres of the sustaining tissues of the alveoli are stretched and a certain amount of the generated workload during inspiration is stored as potential energy in the stretched elastine fibres. The energy necessary for expiration is generated to a large extent by these stretched elastine fibres and a small proportion of the expiration energy is produced by the intercostal muscles and diaphragm. So the total cost of muscle energy during lung ventilation in normal people is minimized very efficiently. . The workload and the VO2max are often reduced in pulmonary patients.[223] The response of the oxygen uptake after the onset of exercise is reduced compared with controls.[223] This is caused by several factors, i.e. a slower rate of increase in skeletal muscle metabolism, a high pulmonary blood flow resistance, and the reduced ability of the pulmonary vascular bed to dilatate to the changed haemodynamics.[223] In chronic obstructive pulmonary disease (COPD) patients, Wasserman[208] showed that the ratio of oxygen uptake/performed workload remained normal compared with controls, but that this ratio was decreased in patients with pulmonary hypertension. In many pulmonary diseases, due to loss of alveolar tissue caused by the process of chronic inflammation, the total alveolar surface area is dramatically reduced. The effect is an increase in dead space. Furthermore, the elastic properties of lung tissue slacken. These lung tissue changes can have dramatic physiological consequences. The diffusion of carbon dioxide is 20 times faster than the diffusion of oxygen.[224] A hampered oxygen diffusion creates in the milder forms of disease a lower arterial oxygen pressure and perhaps also a decrease in arterial haemoglobin saturation. Sports Med 2009; 39 (5)
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In severe forms of hampered diffusion capacity an increased arterial carbon dioxide pressure might occur. For adequate alveolar ventilation the workload of the ‘respiration muscles’ changes to a much more intense one. The respiration muscles are also very active during expiration, in contrast to normal circumstances. Due to the inefficient saturation of haemoglobin, the cardiac muscle has to transport more blood to the organs for an efficient oxygen supply, so cardiac output can be increased. The lung tissue damage can also cause an increase in the total resistance of the capillary bed of the lung, which might create in turn an increase in the blood pressure of the lung arteries. This is an extra workload for the right ventricle of the cardiac muscle. All these pathological changes can create, finally, COPD, the endstage of many prolonged lung diseases. In severe forms of COPD the exercise capacity is reduced dramatically, creating disability. Furthermore, many lung diseases are caused by chronic inflammation accompanied by long-term release of cytokine IL-1, IL-6 and TNF, which act directly on the brain (see figure 5). Beside these changes caused by decreased lung ventilation, changes inside skeletal muscle also occur. [An extensive review of muscle dysfunction in pulmonary disease can be found elsewhere.[225]] Biopsies of the quadriceps muscle (lower limb) of patients with moderate COPD demonstrated atrophy of the type II fibres and a reduction of the type I fibres. It was hypothesized that the chronic hypoxia and the reduced daily activities cause these changes in the muscle cells. Biopsies of the biceps brachii (upper limb) of patients with COPD showed no change in the type I/type II muscle fibre ratio, but the diameter of these fibres was slightly reduced. These histological changes could also be induced by the chronic use of corticosteroids.[201] The final effect of muscle fibre atrophy is reduced muscle mass, which in turn reduces muscle strength. The oxygen content in muscle tissue can be measured with near infrared spectroscopy. Patients with COPD showed a steeper decrease in the muscle tissue oxygen content during exercise than controls. Also, the recovery rate after exercise was longer in COPD patients.[226] These observations sugª 2009 Adis Data Information BV. All rights reserved.
gest a faster and longer muscle tissue hypoxaemia during and after exercise in the COPD patients. 3.1.7 Anaemia
Several diseases cause anaemia, which reduces blood oxygen transport capacity. This reduction . of oxygen capacity negatively affects the VO2max. The effect is that the blood supply to organs has to be increased to supply them with the same amount of oxygen. So at lower workloads cardiac output reaches maximum. Bone marrow malignancies are often accompanied by anaemia. In these circumstances, i.e. malignancy and anaemia, exercise performance could be reduced by several mechanisms (see figure 5). 3.2 Chronic Fatigue Syndrome and Overtraining Syndrome 3.2.1 Chronic Fatigue Syndrome
In patients with chronic fatigue syndrome (CFS) the sense of effort is increased. The exercise performance of these patients compared with controls is conflicting. Some investigators find reduced maximal workloads and maximal heart rates during incremental exercise tests in CFS patients.[227,228] However, during these incremental exercise tests there was no difference in physiological response of different variables like heart rate, maximum oxygen uptake and lactate metabolism with respect to workload.[227-230] So most likely the baseline of the sense of effort is changed in CFS patients, causing reduced maximal exercise performances under ‘normal circumstances’. Some researchers have stated that cytokines might play a role in the pathogenesis of CFS,[231] but others showed no change in the release of the cytokines IL-1 and IL-6 after exercise.[232,233] A systematic check-up by Di Giornio et al.[234] demonstrated a subtle alteration in the hypothalamic-pituitary-adrenal axis (HPA axis). Recently, researchers of the Nijmegen Expert Centre of Chronic Fatigue discovered by MRI a reduced thickness of the cerebral cortex in female patients with CFS.[235] They found a relationship between the level of physical activity capacity and the reduction in grey matter. If their observation is correct, it is important to know which factor is responsible for this reduction. Is this caused by a Sports Med 2009; 39 (5)
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reduction in cortical neurons or by a reduction in the neuron-supporting cells, such as astrocytes? De Lange et al.[235] also suggest that the brain cortex is directly involved in the generation of the sensation of fatigue. It is likely that the fatigue symptoms in CFS patients have a neurological origin, changing the subjects’ perception and changing the circadian rhythm of the HPA axis. 3.2.2 Overtraining Syndrome and the Neuroendocrine System
An example of hormonal effects that may be involved in (central) exercise-related fatigue is given by findings in relation to ‘overtraining’, i.e. a late stage of intense and prolonged training during which the exercise performance declines instead of becoming progressively better. It is hypothesized that, under these conditions, there is a disturbance in the feedback regulation of corticosteroids. In healthy subjects the blood concentration of cortisol decreases in the early stages of a graded exercise and increases in the final stages when [27] During high workloads are being experienced. . exercise levels at about 60% of VO2max, the concentration of cortisol starts to rise after about 1 hour.[236] In the early stages of overtraining in athletes, the adrenal response to corticotropin (adrenocorticotropic hormone) is reduced and finally the HPA axis becomes deregulated, with seriously impaired corticotropin and concomitant cortisol responses.[237] Urhausen et al.[238] measured a higher plasma renin activity at unusually low workloads and a reduced endurance time (»27%) in overtrained .athletes during endurance stress tests (83% of VO2max). This suggests that there might be a link between the neuroendocrine system and higher CNS functions involved in exercise performance and perhaps the sense of effort. Another hypothesis for the cause of overtraining is the chronic mechanical overload from the frequent training sessions, which induces microtrauma. These microtrauma in turn induce a chronic inflammation reaction accompanied by the activation of cytokines, especially IL-6, IL-1 and TNFa. This overtraining model is described by Smith.[239] Steinacker et al.[240] hypothesize ª 2009 Adis Data Information BV. All rights reserved.
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that the skeletal muscle itself produces unknown feedback signals that act at the HPA axis. The symptoms of the overtraining syndrome improve if the intensity of training is reduced or stopped.[241] This phenomenon – reducing or stopping training intensity for a period and the concomitant improvement in overtraining symptoms – is an indication of the protective role of the sensation of fatigue. 4. Conclusions ‘Exercise-induced fatigue’ is a poorly understood phenomenon that intrigues many researchers. Prolonged exercise is a very energy-consuming process, affecting fuel stocks in the long term. Exercise might also have deleterious effects on the homeostasis of the internal environment, causing accumulation of muscle metabolites and of muscle-produced heat. The sensation of fatigue is a psychophysical quantity that eventually will change the subject’s behaviour ‘for their own safety’. Decades ago, the scope of research was entirely just the contracting muscle itself. The mechanical output of the muscle could be reduced by factors within the muscle. Later it was discovered that exercise could introduce an intense shift in the homeostasis of the internal environment. In the last two decades, the CNS has become the main focus of interest. It was shown that exercise induces signs of fatigue in the CNS. New techniques such as transcranial stimulation of the brain cortex by electromagnetic pulses and brain blood flow measurements by functional MRI and PET are important tools for studying the brain during exercise experiments. However, many phenomena remain unclear. It is questionable whether the phenomenon of ‘the sensation of exercise-induced fatigue’ will be fully understood, because it is a conscious awareness. Which structures of our brain are involved in consciousness? The brain cortex plays a very important function in our cognitive skills and perhaps also in awareness of consciousness. However, lower centres of the CNS are necessary for proper functioning of the brain cortex. This means that consciousness, and most likely ‘sense Sports Med 2009; 39 (5)
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of fatigue during exercise’ and ‘motor drive’, are the result of the interaction between many brain centres. A defect in one of these centres might affect one’s exercise properties. We have to realise that ‘exercise-induced fatigue’ and ‘motor drive’ are opposite entities within the scope of interest of both physiologists and psychologists. In the last two decades the physiological effects of cytokines have been investigated. Exercising muscles release IL-6. Several researchers have demonstrated increased blood concentrations of IL-1 and TNF. In athletes, IL-6 causes increased sensations of fatigue during exercise. Many diseases are accompanied by increased levels of IL-1, IL-6 and TNF. IL-1 induces sickness behaviour in animals. Therefore, the effects of the different cytokines on exercise-induced fatigue need to be explored in more detail. Perhaps these cytokines are the key to elucidating the prodromal symptoms of fatigue and malaise during malignancy. Acknowledgements The authors acknowledge the assistance of Karin van der Borght and Izaak den Daas of the Department of Medical Writing of Xendo, in improving the English of this article. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
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