Modulation of PGC-1α activity as a treatment for metabolic and muscle-related diseases

Physical inactivity is a predisposing factor for various disease states including obesity, cardiovascular disease, as well as for certain types of cancer. Regular endurance exercise mediates several beneficial effects such as increased energy expenditure and improved skeletal muscle function, and has been suggested as a therapeutic strategy for both metabolic and muscle‐related disorders. "Exercise mimetic" is a collective term for compounds that can pharmacologically activate pathways which are normally induced during skeletal muscle contraction, and that could be used in the treatment of metabolic or muscle related diseases. Two such experimental "exercise mimetics" are AICAR and resveratrol, which have both been extensively studied in the context of metabolic dysfunction and muscle wasting in rodent disease models. These compounds have been postulated to activate AMP‐activated protein kinase (AMPK) and sirtuin 1 (SIRT1), respectively, in skeletal muscle, and to increase the activation of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α). PGC‐1α can mediate several metabolic and functional adaptations in skeletal muscle in response to physical exercise and is therefore an interesting target for the development of new "exercise mimetic" drugs.