Scientists created a new compound called SLU-PP-332 that activates a protein family (ERRs) important for muscle performance. In mouse studies, the drug boosted mitochondrial activity, shifted muscle fibers toward a more endurance‑friendly type, and let the animals run longer. The effect depended mainly on the ERRα subtype, suggesting it could act like a “exercise pill.”

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERR&#x3b1;, &#x3b2;, and &#x3b3;), and although ERR&#x3b2;/&#x3b3; agonists have been designed, there have been significant difficulties in designing compounds with ERR&#x3b1; agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs <i>in vivo</i>. Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERR&#x3b1;. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an <i>in vivo</i> chemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. We also observed that SLU-PP-332 induced an ERR&#x3b1;-specific acute aerobic exercise genetic program, and the ERR&#x3b1; activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERR&#x3b1; for the development of compounds that act as exercise mimetics that may be effective in the treatment of numerous metabolic disorders and to improve muscle function in the aging.