Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity.
This study identified SLU-PP-332, a synthetic pan-agonist targeting all three estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ), with the highest potency for ERRα. Researchers first characterized the compound's pharmacokinetic properties to confirm it could be used as an in vivo tool. In cultured skeletal muscle cells, SLU-PP-332 was shown to increase mitochondrial function and cellular respiration. In mouse experiments, administration of SLU-PP-332 increased type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. The study also demonstrated that the compound induced a genetic program closely resembling an acute aerobic exercise response, and that this effect was ERRα-dependent — mice lacking ERRα did not show the same enhancement in exercise endurance. The authors propose that targeting ERRα may be a viable strategy for developing exercise mimetics useful in treating metabolic disorders and age-related muscle decline. Key limitations include that all in vivo experiments were conducted in mice, no human data were generated, and the long-term safety and efficacy of SLU-PP-332 remain untested.
Why this grade: All functional in vivo experiments were performed exclusively in mice with supporting in vitro cell-line work; no human subjects or clinical data were included.
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 (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo . 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 ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivo 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 ERRα-specific acute aerobic exercise genetic program, and the ERRα activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERRα 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.
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