Exercise Mimetics

Research into calorie restriction mimetics (drugs which mimic the physiological actions of calorie restriction itself) has opened up interest in other areas, where drugs or compounds may be able to afford the same benefits as the physical action itself. Here, by ‘action’ I mean not only diet, but also exercise or even sex! In a previous IAS publication I discussed calorie restriction mimetics in some detail. Maybe, in the future I will also discuss sex mimetics. But here I will concentrate specifically on compounds which stimulate the body to act as if it was stimulated by the physical action of exercise. The benefits of these compounds are not only relevant to those who may wish to maximise their physical performance but also for people who may be weak, recovering from an operation or have age-related muscle wasting. They should not be seen as an alternative to exercise but as pharmacological alternatives for people who cannot actually exercise due to illness.

During physical exercise there is activation of molecules and genes such AMPK (adenosine monophosphate-activated protein kinase), SIRT1 protein, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) and peroxisome proliferator activator receptor delta (PPARδ). These work in a coordinated way to help remodel the muscle tissue (1). Any agents that can modify the action of these genes or molecules are therefore considered as exercise mimetics.

AICAR

The most publicly-known exercise mimetic is growth hormone, which acts as an anabolic compound that, among other actions, improves muscle mass and strength. But not many members of the public know that an effective and well-studied exercise mimetic is the compound Acadesine, also known as AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide) or Amino-Imidazole Carbox-Amide Ribonucleotide. This is an agonist, i.e. a stimulant, of AMPK and it interferes with the PPARbeta/delta gene which is normally activated during physical exercise, as mentioned above. In one study, researchers who used AICAR in mice have reported that (2):

…..”Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise….”

To reiterate, exercise mimetics should not be seen as a ’workout pill’ but as a useful adjuvant therapy for people who cannot exercise. However, having said that, some people have also been using them to enhance endurance and physical performance. The World Anti-Doping Agency has prohibited the use of AICAR by competing athletes, as it is thought to provide an unfair advantage to the user.

One possible drawback to have in mind is that activation of AMPK may worsen the pro-aging actions of UV light on the skin, with increased production of oxidative compounds and free radical-induced apoptosis.

Erythropoietin

Production of red blood cells is stimulated by erythropoietin. This agent stimulates precursors of red blood cells (such as the pro-erythroblasts) found in the bone marrow, and encourages them to develop into full-grown and active red blood cells, which carry oxygen to the tissues. In this respect, erythropoietin has actions similar to exercise which too affects red blood cells and oxygen-carrying capacity. In addition, erythropoietin stimulates the formation of new blood vessels (angiogenesis) and promotes the function of smooth muscle fibres. In laboratory animals, treatment with erythropoietin was found to protect against brain hypoxia, and it also improves memory and mood (both of which are also improved by physical exercise itself). When skeletal muscle contracts it produces myokines such as IL-6, BDNF and Irisin which may then affect distant organs such as the brain (and hence the biological basis of exercise positively affecting brain function) (3).

Interestingly, researchers have suggested that physical exercise itself may be considered as a drug, which needs to have appropriate dose, frequency and duration, with contraindications and side effects The analogy helps clarify the suggestion that chemical compounds can be used instead, based on the same physiological principle (4).

Lactate

Scientists have shown that lactate can enhance certain genes related to exercise, as well as modify other factors such as RNA expression, not only in the muscles or lungs, but also in the liver and brain. Experiments with mice show that Brain TNF (Tumour Necrosis Factor) fell (with a consequent reduced risk of brain inflammation) and vascular endothelial growth factor increased (which improved the function of the blood vessels) after administration of lactate (5). The concluded:

“ …exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic”.

Some other exercise mimetics

* Carnosine is a well-known booster of muscle activity among its many other benefits (6). I have already discussed this supplement in previous IAS publications.

* Free Fatty Acids (FFA): In an experiment (7), the use of FFA in mice showed a possible role in enhancing other exercise mimetics such as AICAR and also some physiological changes shared with exercise such as regulation of interleukin factors, and muscle-adipose tissue crosstalk.

* Anabolic steroids: It is possible to include anabolic steroids and their derivatives, such as tetrahydrogestrinone and ternbolone, in the class of exercise mimetics, in the sense that these hormones affect muscle mass, appetite and performance. However, due to the fact that many are on the banned list and have serious side effects, I will not discuss these further.

* Resveratrol can be considered as a possible exercise mimetic, which has an effect on enhancing endurance (8). This is thought to be due to activation of the AMPK-SIRT1-PGC-1α pathway.

* Mysotatin inhibitors. Myostatin is a protein that in humans inhibits muscle differentiation and growth, so any compounds which block it would have a positive benefit on muscle growth and function. Myostatin inhibitors are not available for human use but have been used with some success in animals (9).

* Sestrins. These have several effects on metabolism including inhibition of mTOR (discussed in the previous issue of the Magazine), antioxidant actions and AMPK-activation. This is particularly relevant both in exercise and in aging where some changes are shared with those found in non-exercising individuals.

* Arachidonic acid. This contains prostaglandins which may be considered as anabolic compounds that improve metabolism, but are blocked by non-steroidal drugs such as ibuprofen. Athletes using arachidonic acid as a supplement report increased muscle discomfort after exercise, but at the same time, improved endurance and performance.

Major effects of physical exercise secondary effects of exercise

Although there are not yet universally agreed criteria for classifying a compound as an exercise mimetic, I suggest that a compound should be classified as such if it fulfils at least: either three major effects, or two major and two secondary, or one major and five secondary.

Conclusion

Exercise mimetics is a hot area of ageing research and may prove fruitful for weak older patients, those who recover from serious conditions or others who may want to experience a general health-boosting effect. As mentioned in Box 1, the best effect may be achieved with a combination of different mimetics, depending on the exact condition being treated.

References

1. Matsakas A, Narkar VA. Endurance exercise mimetics in skeletal muscle. Curr Sports Med Rep. 2010 Jul-Aug;9(4):227-32

2. Narkar VA, Downes M, et al. AMPK and PPARdelta agonists are exercise mimetics. : Cell. 2008 Aug 8;134(3):405-15

3. Bo H, et al. Exercise and health: from evaluation of health-promoting effects of exercise to exploration of exercise mimetics. Sheng Li Ke Xue Jin Zhan. 2014 Aug;45(4):251-6

4. Vina J, et al. Pharmacological properties of physical exercise in the elderly. Curr Pharm Des. 2014;20(18):3019-29

5. Lu J, Selfridge JE, Burns JM, Swerdlow RH. Lactate administration reproduces specific brain and liver exercise-related changes. J Neurochem. 2013 Oct;127(1):91-100

6. Sale C G et al. Carnosine: from exercise performance to health. 2013, Amino Acids.

7. Sánchez J, Nozhenko Y, Palou A, Rodríguez AM. Free fatty acid effects on myokine production in combination with exercise mimetics. Mol Nutr Food Res. 2013 Aug;57(8):1456-67

8. Hart N et al. Resveratrol enhances exercise training responses in rats selectively bred for high running performance. Food Chem Toxicol. 2013 Nov;61:53-9

9. Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S et al. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength”. Biochem. Biophys. Res. Commun. 2003, 300 (4): 965–71.