A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity

ABSTRACT Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Here we report the identification of a synthetic agonist for the orphan nuclear receptor ERRα (estrogen receptor-related receptor α), SLU-PP-332, that activates an acute aerobic exercise genetic program in skeletal muscle in an ERRα-dependent manner. SLU-PP-332 increases mitochondrial function and cellular respiration consistent with induction of this genetic program. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. These data indicate the feasibility of targeting ERRα for development of compounds that act as exercise mimetics that may be effective in treatment of numerous metabolic disorders and to improve muscle function in the aging.