State Key Laboratory of Molecular Neuroscience, Division of Life Science, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China.
Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, 518055 Shenzhen, China.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2021093118.
Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in -null MuSCs, which induced p53 activation and impaired mTORC1 signaling, leading to defective cell growth, apoptosis, and failure in S-phase reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.
成年老鼠肌肉卫星细胞（MuSCs）在未受伤的肌肉中处于静止状态。当肌肉受伤时，MuSCs 退出静止状态，重新进入细胞周期进行增殖和自我更新，然后分化和融合以驱动肌肉再生。然而，MuSCs 如何从静止状态过渡到循环状态仍然知之甚少。在这里，我们报告 Pax3 和 Pax7 结合蛋白 1（Paxbp1）控制这个关键过渡的一个关键检查点。在成年 MuSCs 中删除 ，它们在受伤后无法重新进入细胞周期，导致完全再生失败。在机制上，我们发现 -null MuSCs 中活性氧（ROS）异常升高，导致 p53 激活和 mTORC1 信号受损，导致细胞生长缺陷、凋亡和 S 期重新进入失败。故意降低 ROS 水平部分挽救了突变 MuSCs 中的细胞周期重新进入缺陷。我们的研究表明，Paxbp1 调节静止 MuSCs 在激活时重新进入细胞周期的晚期细胞生长检查点。
