Duchene muscular dystrophy leads to progressive muscle structural and functional decline due to chronic degenerative-regenerative cycles. Enhancing the regenerative capacity of dystrophic muscle provides potential therapeutic options. We previously demonstrated that the circadian clock repressor Rev-erbα inhibited myogenesis and Rev-erbα ablation enhanced muscle regeneration. Here we show that Rev-erbα deficiency in the dystrophin-deficient mdx mice promotes regenerative myogenic response to ameliorate muscle damage. Loss of Rev-erbα in mdx mice improved dystrophic pathology and muscle wasting. Rev-erbα-deficient dystrophic muscle exhibit augmented myogenic response, enhanced neo-myofiber formation and attenuated inflammatory response. In mdx myoblasts devoid of Rev-erbα, myogenic differentiation was augmented together with up-regulation of Wnt signaling and proliferative pathways, suggesting that loss of Rev-erbα inhibition of these processes contributed to the improvement in regenerative myogenesis. Collectively, our findings revealed that the loss of Rev-erbα function protects dystrophic muscle from injury by promoting myogenic repair, and inhibition of its activity may have therapeutic utilities for muscular dystrophy.

由于慢性退行性再生循环，杜氏肌营养不良症导致进行性肌肉结构和功能衰退。增强营养不良肌肉的再生能力提供了潜在的治疗选择。我们之前证明了生物钟抑制因子 Rev-erbα 抑制了肌生成，而 Rev-erbα 消融增强了肌肉再生。在这里，我们显示了肌营养不良蛋白缺乏的mdx中的 Rev-erbα 缺乏小鼠促进再生肌原性反应以改善肌肉损伤。mdx 小鼠中 Rev-erbα 的缺失改善了营养不良病理和肌肉萎缩。Rev-erbα 缺陷型营养不良肌肉表现出增强的肌原性反应、增强的新肌纤维形成和减弱的炎症反应。在没有 Rev-erbα 的 mdx 成肌细胞中，生肌分化增强，同时 Wnt 信号传导和增殖途径的上调，表明 Rev-erbα 对这些过程的抑制作用的丧失有助于改善再生肌生成。总的来说，我们的研究结果表明，Rev-erbα 功能的丧失通过促进肌源性修复来保护营养不良的肌肉免受损伤，并且抑制其活性可能对肌肉营养不良具有治疗作用。