TY - JOUR AU - Wang, Xun AU - Jia, Yuemeng AU - Zhao, Jiawei AU - Lesner, Nicholas P. AU - Menezes, Cameron J. AU - Shelton, Spencer D. AU - Venigalla, Siva Sai Krishna AU - Xu, Jian AU - Cai, Chunyu AU - Mishra, Prashant T1 - A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle PY - 2022/12/01/ AB - A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of hypoxia-induced factor 1α (HIF1α), which is induced in the setting of muscle damage. Sustained HIF1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of HIF1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint that regulates the speed of myofiber maturation in response to Mfn2 and HIF1α activity. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI161638 VL - 132 IS - 23 UR - https://doi.org/10.1172/JCI161638 PB - The American Society for Clinical Investigation ER -