In a recent review published in Brain Plasticity, researchers discuss the developments in the field of exercise mimetics.
Increased muscle mass, improved circulation, and better brain function are just a few of the rewards obtained with a little sweat. Yet there are many individuals who cannot take part in strenuous workouts due to age, illness, or disability. What if you could have the benefits of exercise without exerting yourself? Enter exercise-mimetics—compounds that could potentially mimic the effects of physical activity.
Exercise consumes the molecule ATP for energy
Physical activity consumes the energy-transporting molecule adenosine triphosphate (ATP) in cells, providing the energy required to power muscle contraction. Certain metabolic enzymes such as AMP Kinase (AMPK) are sensitive to dropping ATP levels. When triggered, the AMPK enzyme shifts the gears of cell metabolism from anabolic (building up) to catabolic (breaking down). This enzyme is part of the AMPK-SIRT1-PGC-1α metabolic pathway. This pathway controls the transcription of genes responsible for many of the beneficial effects of physical exercise.
Compounds that target this pathway, known as exercise mimetics, could theoretically replicate the effects of physical exercise. A review published in Brain Plasticity highlighted recent developments in this field.
Promote blood vessel formation, decrease fat, and lower blood pressure
AICAR is one such compound that occurs naturally in the body and activates AMPK. It can replicate exercise effects by increasing resting energy stores and boosting the number of mitochondria in muscle cells.
Cell and animal studies with AICAR have shown it promotes the formation of new blood vessels (generally associated with endurance exercise), increases liver fat consumption and decreases fat formation, lowering blood pressure. Interestingly, AICAR can also replicate the beneficial effects of exercise on brain function.
In mice, daily dosing with AICAR for one week improved spatial memory and neurogenesis in the short term, but these effects were not sustained for longer periods of time. A possible reason for a lack of sustained effect is that AICAR also increases the release of signalling molecules called cytokines that stimulate inflammatory processes in the brain. Over longer periods of time, these inflammatory processes diminish the beneficial effects gained from AICAR administration.
Metformin affects weight loss, blood pressure, and cognitive decline
Cytokine release can be inhibited by drugs such as metformin, widely prescribed for type 2 diabetes. Through its inhibitory effects, metformin reduces ATP levels which in turn triggers AMPK and its metabolic pathway. Long-term use of metformin can produce weight loss and reduce blood pressure, cholesterol, blood glucose in obese subjects. Metformin has also shown beneficial effects on the brain analogous to exercise.
In mice, treatment for 38 days showed increased neurogenesis and improved memory. Blood vessel and neuron generation were stimulated in mice with stroke. It also exhibited short-term neuroprotective effects in female mice with Alzheimer’s and Parkinson’s disease. However, long-term studies of metformin use in diabetic patients suggest that it may result in a greater cognitive decline, possibly due to interference with vitamin B12 absorption.
Increase cardiovascular endurance and reduce weight gain
Another exercise mimetic compound discussed in the review was GW501516. Originally developed to treat metabolic and cardiovascular diseases, it was abandoned after exhibiting carcinogenic properties in animal studies. Recently it has gained research interest as an exercise mimetic.
GW501516 stimulates PPARδ, a hormone receptor regulating several genes with critical roles in energy regulation and cellular differentiation. PPARδ affects mitochondrial biogenesis, lipid metabolism and oxidative processes, slow and fast twitch muscle fibres, weight reduction, liver glucose generation, and inflammatory regulation.
Studies in mice have shown GW501516 administration can increase cardiovascular endurance by up to 50% in sedentary subjects, and by up to 70% when combined with a running regimen. In obese mice, it reduced the weight gain rate by 50% without reducing food intake, allowing them to eat the same amount of food but gain weight slower.
Given the long-term risks associated with the above drugs, the study authors also reviewed dietary supplements. Peanuts, berries and grapes contain the compound resveratrol, which activates AMPK and has anti-inflammatory, antioxidative and mitochondria boosting effects.
In studies on mice with high-fat diets, resveratrol increased oxygen consumption, aerobic capacity and insulin sensitivity. It also reduced oxidative stress damage to muscle fibres in both young and old mice.
Exercise can’t be replaced
The review authors highlight that the benefits of exercise are likely not replaceable by a single pill, and maintain that being physically active is still preferable, due to the side effects of prolonged use of mimetics.
These drugs could still be combined with light physical training as a temporary solution until patients are able to perform more demanding exercises. Ongoing research in this field is especially relevant for patients with obesity or neurodegenerative diseases, where immediate heavy exercise is not an option.
Guerrieri D, Moon HY, van Praag H. Exercise in a pill: The latest on exercise-mimetics. Brain Plasticity. 2017 Mar 28;2(2):153-169. doi:10.3233/BPL-160043.