A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-12-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI161638 |
| _version_ | 1797634483013287936 |
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| author | Xun Wang Yuemeng Jia Jiawei Zhao Nicholas P. Lesner Cameron J. Menezes Spencer D. Shelton Siva Sai Krishna Venigalla Jian Xu Chunyu Cai Prashant Mishra |
| author_facet | Xun Wang Yuemeng Jia Jiawei Zhao Nicholas P. Lesner Cameron J. Menezes Spencer D. Shelton Siva Sai Krishna Venigalla Jian Xu Chunyu Cai Prashant Mishra |
| author_sort | Xun Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:27Z |
| format | Article |
| id | doaj.art-15b0cd65a0394ce191cd116aa3a38eda |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:27Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-15b0cd65a0394ce191cd116aa3a38eda2023-11-07T16:19:33ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-12-0113223A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscleXun WangYuemeng JiaJiawei ZhaoNicholas P. LesnerCameron J. MenezesSpencer D. SheltonSiva Sai Krishna VenigallaJian XuChunyu CaiPrashant MishraA 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.https://doi.org/10.1172/JCI161638Muscle biologyStem cells |
| spellingShingle | Xun Wang Yuemeng Jia Jiawei Zhao Nicholas P. Lesner Cameron J. Menezes Spencer D. Shelton Siva Sai Krishna Venigalla Jian Xu Chunyu Cai Prashant Mishra A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle The Journal of Clinical Investigation Muscle biology Stem cells |
| title | A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| title_full | A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| title_fullStr | A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| title_full_unstemmed | A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| title_short | A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| title_sort | mitofusin 2 hif1α axis sets a maturation checkpoint in regenerating skeletal muscle |
| topic | Muscle biology Stem cells |
| url | https://doi.org/10.1172/JCI161638 |
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