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Editorials
Are ‘‘exercise pills’’ the answer to the growing problem of physical inactivity? Stuart J Warden, Robyn K Fuchs Physical inactivity is an important and growing major health concern and is defined as not engaging in any regular pattern of physical activity beyond that associated with daily functioning.1 The many consequences of inactivity include reductions in insulin sensitivity of skeletal muscle and expansion of fat storage, factors associated with the development of obesity, metabolic syndrome and type 2 diabetes.2 Exercise is often performed with the goal of counteracting these changes and enhancing health and life expectancy. Imagine if the health benefits of exercise could be produced simply by taking a so-called ‘‘exercise pill’’. This would be every couch potato’s dream and may be a reality if a paper recently published in the prestigious journal Cell is any indication.
DISCOVERING THE ‘‘MAGIC BULLET’’? Narkar et al3 investigated the benefits of two orally active compounds on exercise endurance in mice. The first compound, known simply as GW1516, did not enhance endurance when given to sedentary mice, but when combined with a progressive treadmill exercise programme, it enabled mice to run 60–75% further and longer than mice exposed to the exercise programme alone. Thus, there was synergy between exercise and GW1516, whereby GW1516 ‘‘supercharged’’ the endurance phenotype generated by exercise. Although this is impressive, more striking were the results obtained with a second compound, known as 59-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR). When administered for 4 weeks to sedentary mice, AICAR increased running time and distance during a treadmill endurance test by 23% and 44%, respectively. That is, AICAR was able to induce Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana, USA Correspondence to: Dr Warden, Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, 1140 W. Michigan St, Indianapolis, IN, CF-326 USA;
[email protected] 862
endurance benefits without the mouse undertaking a single exercise session! The mechanisms by which GW1516 and AICAR enhance endurance are not entirely clear, but indications are that the compounds work by genetically reprogramming skeletal muscle metabolism. This is achieved via two closely-linked proteins, with GW1516 being an agonist of peroxisome proliferator-activated receptor delta (PPARd) and AICAR being an agonist of AMP-activated protein kinase (AMPK). Both proteins regulate the expression of genes within skeletal muscle that are primarily associated with oxidative metabolism.4 5 The downstream effect is that both PPARd and AMPK make myofibres more energy-efficient and fatigue-resistant by reducing glycogen dependency and increasing fatty acid oxidation. In clinical parlance it would be fair to say that they essentially modify the myofibril phenotype from glycolytic fast-twitch (type IIB) to more oxidative slow-twitch (type I). The ability of AICAR to bring about functional changes (ie, enhance endurance) when administered in isolation fits with the hypothesized role of AMPK as the master regulator of cellular energy balance.5 6 AMPK is activated by an increase in the intracellular AMP:ATP ratio associated with metabolic stress (ie, exercise) and alters gene expression to restore energy balance by both enhancing ATP-producing catabolic processes and suppressing ATP-consuming anabolic pathways.7 By administering AICAR, myofibres are ‘‘tricked’’ into thinking they are in a state of energy deficit (ie, have been exercised). The same does not occur with the isolated introduction of GW1516, as it appears to require activation of AMPK in order to elicit its functional benefit. This can be achieved via co-administration of GW1516 with either exercise or AICAR.3 Based on the observation that GW1516 and AICAR produce changes in skeletal muscle consistent with those induced by exercise, Narkar et al3 concluded that the two compounds are exercise mimetics or
so-called ‘‘exercise pills’’. Unfortunately, there is no such thing as an exercise pill and probably never will be, because the term is a misnomer.8–10 Exercise has multisystem effects and it is highly unlikely that a single compound or pathway is responsible for its effects in every system. Consequently, no pharmaceutical agent with a single molecular target will be able to produce all of the beneficial effects generated with actual physical activity. Supporting this, AICAR has not been shown to produce all of the changes induced by exercise in skeletal muscle.11 In addition, it has not yet been shown to have exercise-mimicking effects in tissues beyond skeletal muscle. Its exercise-like effects within the cardiovascular, central nervous and other systems need to be demonstrated before the term exercise pill can even be considered.
ONE-DIMENSIONAL EFFECTS ARE A MAJOR LIMITATION OF PILLS So-called exercise pills are not the answer to the growing societal problem of physical inactivity. In fact, the simple and relatively passive act of ingesting a pill with the belief that it mimics exercise may actually perpetuate the problem by encouraging individuals to cease all physical activity beyond that associated with daily functioning. This could lead to inactivity-related pathologies and chronic diseases if the pill taken cannot precisely produce every physiological change associated with exercise.8 The reality is that if you want to achieve the health benefits of exercise, then you need to exercise. However, this does not mean that pharmaceutical agents that produce at least some of the benefits of exercise do not have substantial clinical potential. For instance, GW1516 and AICAR may bring about desirable changes in fat and glucose metabolism to treat or offset the development of obesity, metabolic syndrome and type 2 diabetes. AICAR may be able to do this in people who cannot exercise for whatever reason, and GW1516 may augment the normal response to exercise to induce greater adaptation than with exercise alone. The later does raise a legitimate concern of substance abuse by athletes who desire a competitive advantage, but tests are reportedly available for detecting both GW1516 and AICAR and their metabolic by-products. Although compounds such as GW1516 and AICAR may not be actual exercise pills, their development and that of similar substances may improve health and life expectancy in susceptible subgroups of Br J Sports Med November 2008 Vol 42 No 11
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Editorials the population if their demonstrated effects in preclinical animal studies can be translated to the clinical setting.
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Competing interests: None. Accepted 10 September 2008
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Br J Sports Med 2008;42:862–863. doi:10.1136/bjsm.2008.053512 5.
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Centers for Disease Control and Prevention. Glossary of terms. http://www.cdc.gov/nccdphp/dnpa/ physical/everyone/glossary/index. htm#Other%20Terms (Accessed 19 September 2008).
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Booth FW, Laye MJ, Lees SJ, et al. Reduced physical activity and risk of chronic disease: the biology behind the consequences. Eur J Appl Physiol 2008;102:381–90. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134:405–15. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590–7. Osler ME, Zierath JR. Adenosine 59-monophosphateactivated protein kinase regulation of fatty acid oxidation in skeletal muscle. Endocrinology 2008;149:935–41. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8:774–85.
Jumping on bandwagons: taking the right clinical message from research Jill Cook The prime goal of clinical research is to inform and direct practice, although a general practitioner friend of mine insists that ‘‘bloody academics’’ do nothing worthwhile for the world in general or for clinicians specifically. Despite that opinion, research has consistently improved practice across all disciplines in sports medicine. There are, however, instances where clinical practice has steamed ahead of research knowledge. Experienced practitioners will recall the thousands of dollars spent on isokinetic machines in the 1980s and note that only slightly less is currently being spent on Pilates-based exercise machines. Both isokinetic training and Pilates exercise are excellent modes of rehabilitation, and the equipment can provide very positive gains. However, claims for the effectiveness of these modalities have been touted well beyond what the research has shown. There has been excellent and ongoing research into the rehabilitation of low back pain which has focused on muscle strengthening and conditioning; hence the current clinical use of Pilates-based rehabilitation. The role of transversus abdominis as a key stabiliser of the lumbar spine has been extensively reported and clinicians have taken this to heart. As a result, transversus abdominis conditioning, Pilates and ‘‘core stability’’ are basic tenets for the rehabilitation of low back pain, as Correspondence to: Jill Cook, Musculoskeletal Research Centre, Deakin University, 221 Burwood Highway, Melbourne 3025, Australia;
[email protected]
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well as for various upper and lower limb injuries. This can have clinical benefit, but recent research reported in this issue by Allison et al suggests that transversus abdominis may work unilaterally in response to spinal rotations rather than as a premovement bilateral stabiliser. Does this mean that the hours spent teaching and practising isolated, bilateral activation of transversus abdominis may not have been the most effective use of time? Maybe it does, but transversus abdominis exercise now has a life of its own; it has gone beyond sports medicine and physiotherapy into fitness and gymbased programmes. If research confirms that transversus abdominis exercise does not contribute to spinal health as a bilateral stabiliser, it will nevertheless take years to undo what has already been taught in the community. Although there appear to be no harmful consequences from time spent on transversus abdominis exercise, exercise time is precious for most people, so using it on effective exercises is clearly ideal. Clinically, the translation from basic transversus abdominis research to improved outcomes for injured individuals has, to date, been less than inspiring. Few studies have shown that abdominal muscle strengthening or activation contributed to reducing low back pain, or that lack of core stability was causally associated with injury, or even that isolated muscle strengthening translated into muscle use in everyday activity. So where to from here for clinicians? Do we abandon the last 10 years of teaching
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Hardie DG, Salt IP, Hawley SA, Davies SP. AMPactivated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 1999;338:717–22. Booth FW, Lees SJ. Fundamental questions about genes, inactivity and chronic diseases. Physiol Genomics 2007;28:146–57. Richter EA, Kiens B, Wojtaszewski JF. Can exercise mimetics substitute for exercise? Cell Metab 2008;8:96–8. Williams RS, Kraus WE. Exercise and health: can biotechnology confer similar benefits? PLoS Med 2005;2:e68. Rantzau C, Christopher M, Alford FP. Contrasting effects of exercise, AICAR and increased fatty acid supply on in vivo and skeletal muscle glucose metabolism. J Appl Physiol 2008;104:363–70.
transversus abdominis exercises in clinical practice, and, if so, what do we put in its place? Exercise has a central place in rehabilitation, and loading the musculoskeletal system results in gains through tissue strengthening. Virtually any exercise has benefits, and, although the precise role of transversus abdominis is not yet clearly understood, there is certainly no evidence that the transversus abdominis exercises as taught are not beneficial in some way. If they are not beneficial locally, they may produce benefits more globally through associated abdominal muscle activity. Bandwagons have a purpose, otherwise people would not embark. One benefit is that they allow for the rapid dissemination of certain clinical protocols and they allow clinicians to feel that they are giving the best ‘‘evidence-based’’ treatments. Perhaps, as Allison says, we should qualify statements of efficacy more and perhaps be less absolute in how we explain treatment to clients.1 That way, we can continue to incorporate new research findings in clinical practice without being inaccurate about research findings. For transversus abdominis exercises, this would mean stating that transversus abdominis has a role in the treatment of low back pain but that it is not solely responsible for ‘‘core stability’’. We should probably avoid suggesting that ‘‘core stability’’ exercises provide the absolutely specific treatment that will resolve back pain and improve function. Although research has a key role in guiding clinicalpractice, clinicians also play a key role in translating that research. There is responsibility on both sides of the equation. Competing interests: None declared. Accepted 3 April 2008 Published Online First 7 May 2008 Br J Sports Med 2008;42:863. doi:10.1136/bjsm.2008.048629
REFERENCE 1.
Allison GT. Consider the alternative. J Orthop Sports Phys Ther 2007;37:153–4.
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