Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.
Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, New Territories, Hong Kong SAR, China.
Nat Commun. 2023 Aug 17;14(1):4978. doi: 10.1038/s41467-023-40465-w.
Skeletal muscle stem cells (also called satellite cells, SCs) are important for maintaining muscle tissue homeostasis and damage-induced regeneration. However, it remains poorly understood how SCs enter cell cycle to become activated upon injury. Here we report that AP-1 family member ATF3 (Activating Transcription Factor 3) prevents SC premature activation. Atf3 is rapidly and transiently induced in SCs upon activation. Short-term deletion of Atf3 in SCs accelerates acute injury-induced regeneration, however, its long-term deletion exhausts the SC pool and thus impairs muscle regeneration. The Atf3 loss also provokes SC activation during voluntary exercise and enhances the activation during endurance exercise. Mechanistically, ATF3 directly activates the transcription of Histone 2B genes, whose reduction accelerates nucleosome displacement and gene transcription required for SC activation. Finally, the ATF3-dependent H2B expression also prevents genome instability and replicative senescence in SCs. Therefore, this study has revealed a previously unknown mechanism for preserving the SC population by actively suppressing precocious activation, in which ATF3 is a key regulator.
骨骼肌干细胞（也称为卫星细胞，SCs）对于维持肌肉组织的内稳态和损伤诱导的再生至关重要。然而，SCs 如何进入细胞周期并在受伤时被激活仍然知之甚少。在这里，我们报告 AP-1 家族成员 ATF3（激活转录因子 3）可防止 SC 过早激活。Atf3 在 SC 被激活后迅速且短暂地诱导。SCs 中短期删除 Atf3 可加速急性损伤诱导的再生，然而，其长期删除会耗尽 SC 池，从而损害肌肉再生。Atf3 的缺失还会在自愿运动期间引发 SC 激活，并在耐力运动期间增强激活。在机制上，ATF3 直接激活组蛋白 2B 基因的转录，其减少加速了核小体位移和 SC 激活所需的基因转录。最后，ATF3 依赖性 H2B 表达还可防止 SC 中的基因组不稳定性和复制性衰老。因此，这项研究揭示了一种通过积极抑制早熟激活来维持 SC 群体的先前未知机制，其中 ATF3 是关键调节因子。
