Exercise Mimetics: Fact or Fallacy?
When we think of exercise pills, we think of scientists in their laboratories concocting tonics and magic tablets containing all the benefits of exercise in a tiny capsule. We can’t imagine this ever becoming a reality because, to us, getting and staying in shape involves forcing our way through endless sets of squats and sit-ups, day after day in the gym. The idea of the exercise pill first hit the headlines around 2004 when a Californian Lab suggested that organ-specific exercise training effects could be mirrored by certain chemical particles and to date the term ‘’exercise pill’’ when typed into a google search engine retrieves a staggering 100,000,000 results, ensuing an understandable level of confusion among health practitioners, sporting coaches and athletes alike. So, the question prevails - what is fact, and what is fallacy?
Drugs which mimic the effects of exercise have the potential to not only improve sporting performance, and prevent muscle wasting during injury, but to potentially combat obesity and other metabolic conditions and diseases. Understanding how exercise training exerts its beneficial effects remains to be fully understood. However, it is widely accepted that skeletal muscle plays a pivotal role in the process. Accounting for around 40% of the total body weight and utilising 30% of the body’s energy whilst at rest, the skeletal muscle is a mosaic of different muscle fibers accounting for its various structural and functional properties. These structural differences are the reason behind the stark contrast in appearance between sprinters like Tyson Gay and marathon runners like Stephen Kiprotich.
There are several types of muscle fibers – Type I (slow-twitch) and Type II (fast-twitch). Type I fibers are rich in energy factories known as mitochondria and are resistant to fatigue. In comparison, the glycolytic Type II fibres contain fewer mitochondria and are more susceptible to fatigue. The importance of understanding these fiber types is that with exercise training comes a fiber-type transformation. Both sprint/power training and endurance/aerobic training elicit different muscle adaptations such as muscle accretion in strength/resistance training and mitochondrial adaption in endurance training. This is due to the changes which occur in biomolecules within the muscle cells. Depending on the exercise type, different changes (protein and enzyme activity) occur within our muscle. These proteins and enzymes are the molecular targets for scientists when looking at exercise mimetics. Briefly, a stimulus (exercise), conveys a message to the cell (through a cell receptor). A series of proteins and reactions pass this message through the cell until it eventually reaches the cell brain, or the nucleus. This message is decoded and the cell can then decide how to respond. This is known as signal transduction. Any of the molecules along this series of chain reactions makes them ideal pharmacological targets for mirroring the effects seen when exercise provokes the chain reactions.
Endurance training results in fast-to-slow fiber type transformation and mitochondrial biogenesis. AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) is a prospective exercise pill whose effects result in potential enhancements of endurance capacity. This molecule specifically targets a protein called AMPK (AMP- activated protein Kinase). AMPK, when activated, shuts off energy-expensive processes (protein and glycogen formation), whilst simultaneously promoting the utilisation of glucose and fat for energy. Dr. Ronald Evans and his lab tested the use of AICAR in a sedentary mouse models and after 4 weeks noted an increase in endurance capacity of up to 44%. The activation of AMPK results in the interaction with another protein known as PGC-1a, triggering the formation of new mitochondria as well as fiber type transformation within the skeletal muscle. The research group also eluded to another potential exercise pill, GW1516, a substance which can interact with PPARδ, another molecule involved in skeletal muscle metabolism. It was demonstrated that increased PPARδ activity led to heightened endurance capacity by almost 100%, but only when combined with exercise. It was further demonstrated that GW1516 and AICAR, when combined, produce effects greater than if either substance was used individually, potentially yielding a polypill. In addition to improving endurance capacity, GW1516 treatment in monkeys demonstrated improved blood cholesterol. This improvement in the ‘good cholesterol’ profile in the blood is generally seen in athletes and may be a therapeutic option for obesity or type 2 diabetes. A drug currently on the market, metformin, exhibits part of its action through the stimulation of AMPK and thus lowering blood-glucose in patients with Type 2 diabetes.
Aside from AMPK, a study published in a highly prestigious journal, Nature Medicine, identified Rev-erb-α as a key player in muscle endurance capacity and a possible pharmacological target to enhance muscle function. Here researchers overexpressed Rev-erb-α in mice and saw weight loss and improvements in cholesterol levels, regardless of high-fat diet or low-fat diet group. Woldt and colleagues also generated mice with low levels of Rev-erb-α, which created un-athletic mice with lower VO2 max when compared to their normal littermates. The effect was not replicated in muscle with impaired function.
Recently, certain foods have developed reputations that consuming them can elicit benefits equal to an hour in the gym – this is particularly seen with Red Wine and Dark Chocolate. These articles are sensationalising the truth that particular compounds in red wine and chocolate have the ability to elicit exercise mimicking effects when consumed in huge quantities. In one study, resveratrol (found in red wine, blueberries and grapes) was fed (200 or 400 mg/kg/day) to mice for 15 weeks and after this period the mice consuming the high-fat diet and resveratrol had not gained any excess weight when compared to the mice on low-fat diet. This effect was via AMPK activation, similar to exercise. Discrepancies have arisen among research groups as to whether the effect of resveratrol is a true one, however this may be down to the varying doses used in studies. Further research is definitely necessary before this compound is considered as an exercise mimetic.
Moving from the muscle of Stephen Kiprotich to Tyson Gay – resistance/strength training results in the stimulation of processes leading to muscle mass accretion and muscle hypertrophy. The concept of an exercise mimetic in this area would be particularly useful for elderly individuals suffering from muscle wasting conditions. Taking a pill to gain muscle mass may seem to be more straight forward given the range of nutritional supplements on the shelves promising lean results. The myokine Myostatin acts to stop muscle growth by inhibiting this molecule, with a substance called follistatin, we can accumulate muscle mass. This is currently a prominent solution under clinical investigation for muscle wasting disorders.
So after all that science, you are asking me ‘How does this all relate to real life?’… I guess the concept of exercise-mimicking pills is a good one in principle, but in reality there is much left to be revealed. Developing exercise mimetics down the line may be a saviour for cancer cachexia patients, individuals with sarcopenia or those unable to exercise due to spinal injuries and obesity.
If you are reading this and hoping that you could cheat your way around actual exercise, you may want to reconsider as these so-called exercise mimetics are banned in the sporting world.
When you delve deeper behind the sensational headlines of ‘The Exercise Pill’, you can pick apart the flaws around the practicality of the idea. Even the term exercise mimetic is flawed! Mimicking exercise involves replicating the multitude of pathways and physiological responses evoked by a bout of exercise – this is simply unachievable using any one of these substances mentioned. Health benefits and adaptions such as prevention of osteoporosis, injuries as a result of falling, neurological conditions like dementia, improvements in blood pressure, the release of endorphins and the amelioration of conditions like depression and anxiety remain AWOL. So we can hardly use the term exercise mimicking pills when this vast range of benefits are left out!
Secondly, the vast majority of science backing these dramatic headlines is carried out in highly controlled mouse models. Many of the studies examining gene deletion in mice do not account for the possibility that another protein in the cell may compensate for the loss of another – suggesting that a king of all exercise genes is doubtful to exist. Whilst obviously beneficial to understand the molecular mechanisms of the drug, difficulties prevail in the translation of these results into a human model so results must be interpreted with caution.
Adverse side effects are sometimes shoved aside in the search for this wonder drug. These are difficult to ascertain due to the lack of human studies. Also, the consequences as a result of over/under expression of certain body molecules are occasionally forgotten. Every protein in the body has a role to play and has adapted through evolution, potentially making a whole body target detrimental to systems like the immune systems.
The processes that occur after exercising are enormously complex with hundreds of pathways and thousands of molecules having a part to play. Deciphering the code which is exercise metabolism is no doubt a key to unlocking the true concept of exercise mimetics. Not one of the pills mentioned are able to offer the full palette of benefits associated with actual exercise, however in specific populations this may be the next best option. In other words, for those of us pouring the second glass of wine and waiting for this miracle pill – hold on to them Nike Frees!