| First Author | Wang X | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 23 | PubMed ID | 36125902 |
| Mgi Jnum | J:332020 | Mgi Id | MGI:7408037 |
| Doi | 10.1172/JCI161638 | Citation | Wang X, et al. (2022) A mitofusin 2/HIF1alpha axis sets a maturation checkpoint in regenerating skeletal muscle. J Clin Invest 132(23) |
| abstractText | 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 1alpha (HIF1alpha), which is induced in the setting of muscle damage. Sustained HIF1alpha 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 HIF1alpha 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 HIF1alpha activity. |
