The open access paper noted here reviews some of the known molecular targets for the development of exercise mimetics. An exercise mimetic is a therapy that in some way triggers a fraction of the beneficial cellular response to exercise. Exercise mimetic development lags behind calorie restriction mimetic development, and both are very slow, very expensive lines of work with - so far - little to show in terms of practical, useful therapies. It remains the case that it is far easier and better to actually exercise or practice calorie restriction. Even when the first truly effective therapies are available in the clinic, and it must be said there is no real sign that this will happen before the late 2020s, they are unlikely to be as beneficial as either exercise or calorie restriction. The cellular response to stress is very complex and includes many distinct mechanisms; efforts to produce mimetic drugs tend to focus down on only a fraction of those mechanisms.
Exercise benefits young and old organisms, including increased skeletal mass, improvement in the cardiovascular system, and metabolic regulation, as well as in brain functions associated with cognition, memory, and mood. In particular, exercise promotes adult hippocampal neurogenesis and neuronal plasticity, and is associated with increased memory performance and cognition, and is considered to counter cognitive decline caused by aging and by neurodegenerative diseases.
Skeletal muscle is the most abundant tissue in the human body and the most highly activated organ in response to physical activity. Aerobic exercise affects skeletal muscle by inducing a substantial switch in composition from fast-twitching, glycolytic type IIb fibers to the more oxidative, slow-twitching type I fibers. Endurance training results in an increase in mitochondrial biogenesis and activity, vascularization, oxygen consumption and an overall improvement of aerobic capacity. Furthermore, the resulting activation of signaling pathways relevant to energy metabolism, such as the AMPK-SIRT1-PGC-1α pathway in muscle may contribute to the benefits of exercise for brain function.
The vast beneficial consequences of exercise might not be within reach of debilitated, diseased, and elderly patients. The development of compounds capable of activating cellular targets of exercise may be a new therapeutic approach. Indeed, recent research indicates that factors secreted by skeletal muscle during exercise may exert beneficial effects on brain function. This review will focus on the identified targets relevant to energy metabolism in muscle and the molecules affecting it.
An active lifestyle, despite the promising of compounds currently under study, remains the preferred choice for improving body and brain function. Indeed, the mechanisms of action of exercise mimetics still require further investigation, and the possibility of a treatment capable of replacing exercise in its entirety is remote. In order to achieve an artificial exercise regimen, potential adverse effects of prolonged treatment with exercise mimetics have to be overcome. Nonetheless, a possible use of this class of compounds could be envisioned in parallel with light training paradigms, helping to achieve a more complete exercise-induced benefit, both on brain and on peripheral functions. This is especially poignant for conditions, such as morbid obesity or neurodegenerative diseases, which may preclude exercise.