Study summary · research use only
Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in mice and a skeletal muscle cell line examined SLU-PP-332, a synthetic pan agonist of the estrogen receptor-related receptors (ERRα, β, and γ) with highest potency at ERRα. SLU-PP-332 was associated with increased mitochondrial function and cellular respiration in the skeletal muscle cell line. When administered to mice, SLU-PP-332 was associated with increased type IIa oxidative skeletal muscle fibers and longer exercise endurance, and the authors report that ERRα activation specifically induced an acute aerobic exercise gene program and was necessary for the endurance-related effect. The authors describe these findings as indicating the feasibility of targeting ERRα to develop exercise-mimetic compounds for metabolic disorders and muscle function in aging.
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. 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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