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ResearchIn-Press PreviewMuscle biologyStem cells Open Access | 10.1172/JCI161638
1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
Find articles by Wang, X. in: JCI | PubMed | Google Scholar |
1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
Find articles by Jia, Y. in: JCI | PubMed | Google Scholar
1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
Find articles by Zhao, J. in: JCI | PubMed | Google Scholar |
1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America
4Children's Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America
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Published September 20, 2022 - More info
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 which pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), whose expression 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 which regulates the speed of myofiber maturation in response to Mitofusin 2 and Hif1α activity.