Skeletal muscle SIRT1 and the genetics of metabolic health: therapeutic activation by pharmaceuticals and exercise.

Silent mating type information regulation 2 homolog 1 (SIRT1) is implicated in the control of skeletal muscle mitochondrial content and function through deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and participation in the SIRT1/PGC-1α axis. The SIRT1/PGC-1α axis control of skeletal muscle mitochondrial biogenesis is an important therapeutic target for obesity and obesity-related metabolic dysfunction, as skeletal muscle mitochondrial dysfunction is implicated in the pathogenesis of multiple metabolic diseases. This review will establish the importance of the SIRT1/PGC-1α axis in the control of skeletal muscle mitochondrial biogenesis, and explore possible pharmacological and physiological interventions designed to activate SIRT1 and the SIRT1/PGC-1α axis in order to prevent and/or treat obesity and obesity-related metabolic disease. The current evidence supports a role for therapeutic activation of SIRT1 and the SIRT1/PGC-1α axis by both pharmaceuticals and exercise in the treatment and prevention of metabolic disease. Future research should be directed toward the feasibility of pharmaceutical activation of SIRT1 in humans and refining exercise prescriptions for optimal SIRT1 activation.