兴奋剂
骨骼肌
受体
体内
药理学
运动生理学
耐力训练
内分泌学
化学
内科学
医学
生物
生物技术
作者
Cyrielle Billon,Sadichha Sitaula,Subhashis Banerjee,Ryan D. Welch,Bahaa Elgendy,Lamees Hegazy,Tae Gyu Oh,Melissa Kazantzis,Arindam Chatterjee,John C. Chrivia,Matthew Hayes,Weiyi Xu,Angelica Hamilton,Janice M. Huss,Lilei Zhang,John K. Walker,Michael Downes,Ronald M. Evans,Thomas P. Burris
标识
DOI:10.1021/acschembio.2c00720
摘要
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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