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Are “exercise pills” the answer to the growing problem of physical inactivity?
  1. Stuart J Warden,
  2. Robyn K Fuchs
  1. Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana, USA
  1. Dr Warden, Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, 1140 W. Michigan St, Indianapolis, IN, CF-326 USA; stwarden{at}

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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.


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 5′-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 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 (PPARδ) 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 PPARδ 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.810 Exercise has multi-system 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.


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 the population if their demonstrated effects in preclinical animal studies can be translated to the clinical setting.


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  • Competing interests: None.

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