The process of tissue regeneration occurs in a developmentally timed manner, yet the role of circadian timing is not understood. Here, we identify a role for the adult muscle stem cell (MuSC)-autonomous clock in the control of muscle regeneration following acute ischemic injury. We observed greater muscle repair capacity following injury during the active/wake period as compared with the inactive/rest period in mice, and loss of Bmal1 within MuSCs leads to impaired muscle regeneration. We demonstrate that Bmal1 loss in MuSCs leads to reduced activated MuSC number at day 3 postinjury, indicating a failure to properly expand the myogenic precursor pool. In cultured primary myoblasts, we observed that loss of Bmal1 impairs cell proliferation in hypoxia (a condition that occurs in the first 1–3 d following tissue injury in vivo), as well as subsequent myofiber differentiation. Loss of Bmal1 in both cultured myoblasts and in vivo activated MuSCs leads to reduced glycolysis and premature activation of prodifferentiation gene transcription and epigenetic remodeling. Finally, hypoxic cell proliferation and myofiber formation in Bmal1-deficient myoblasts are restored by increasing cytosolic NAD⁺. Together, we identify the MuSC clock as a pivotal regulator of oxygen-dependent myoblast cell fate and muscle repair through the control of the NAD⁺-driven response to injury.

中文翻译：

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BMAL1通过控制卫星细胞中的低氧NAD+再生来驱动肌肉修复

组织再生的过程以发育定时的方式发生，但昼夜节律的作用尚不清楚。在这里，我们确定了成人肌肉干细胞 (MuSC) 自主时钟在控制急性缺血性损伤后肌肉再生中的作用。我们观察到与小鼠的非活动/休息期相比，在活动/清醒期受伤后的肌肉修复能力更强，并且MuSC 内Bmal1的缺失导致肌肉再生受损。我们证明， MuSC 中的Bmal1损失导致受伤后第 3 天激活的 MuSC 数量减少，表明未能正确扩展肌源性前体池。在培养的原代成肌细胞中，我们观察到Bmal1的缺失损害缺氧条件下的细胞增殖（这种情况发生在体内组织损伤后的前 1-3 天），以及随后的肌纤维分化。培养的成肌细胞和体内激活的 MuSC中Bmal1的缺失导致糖酵解减少和前分化基因转录和表观遗传重塑的过早激活。最后，Bmal1缺陷型成肌细胞中的低氧细胞增殖和肌纤维形成通过增加细胞溶质 NAD ⁺得以恢复。^{总之，我们通过控制 NAD +}驱动的损伤反应，将 MuSC 时钟确定为氧依赖性成肌细胞命运和肌肉修复的关键调节因子。