Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity,ACS Chemical Biology

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Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2023-03-29 , DOI: 10.1021/acschembio.2c00720
Cyrielle Billon ₁ , Sadichha Sitaula ₁ , Subhashis Banerjee ₂ , Ryan Welch ₃ , Bahaa Elgendy ₁ , Lamees Hegazy ₁ , Tae Gyu Oh ₃ , Melissa Kazantzis ₄ , Arindam Chatterjee ₂ , John Chrivia ₂ , Matthew E Hayes ₅ , Weiyi Xu ₆ , Angelica Hamilton ₇ , Janice M Huss ₇ , Lilei Zhang ₆ , John K Walker _{2,

8} , Michael Downes ₃ , Ronald M Evans _{3,

9} , Thomas P Burris _{1,

5}

Affiliation

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.

中文翻译：

合成 ERRα/β/γ 激动剂诱导 ERRα 依赖性急性有氧运动反应并增强运动能力

重复的体育锻炼会诱导骨骼肌的生理适应，从而提高运动表现，并有效预防和治疗多种疾病。遗传证据表明，孤儿核受体雌激素受体相关受体（ERRs）在骨骼肌运动能力中起重要作用。存在三种 ERR 亚型（ERRα 、 β 和 γ），尽管已经设计了 ERRβ/γ 激动剂，但在设计具有 ERRα 激动剂活性的化合物方面存在重大困难。此外，可用于在体内靶向 ERR 的合成激动剂有限。在这里，我们报告了一种合成 ERR 泛激动剂 SLU-PP-332 的鉴定，该激动剂靶向所有三种 ERR，但对 ERRα 具有最高效力。此外，SLU-PP-332 具有足够的药代动力学特性，可用作体内化学工具。SLU-PP-332 增加骨骼肌细胞系中的线粒体功能和细胞呼吸。当施用于小鼠时，SLU-PP-332 增加了 IIa 型氧化骨骼肌纤维并增强了运动耐力。我们还观察到 SLU-PP-332 诱导 ERRα 特异性急性有氧运动遗传程序，ERRα 激活对于增强小鼠的运动耐力至关重要。这些数据表明靶向 ERRα 开发作为运动模拟物的化合物的可行性，这些化合物可能有效治疗多种代谢紊乱并改善衰老中的肌肉功能。

更新日期：2023-03-29

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