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A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle
Xun Wang, … , Chunyu Cai, Prashant Mishra
Xun Wang, … , Chunyu Cai, Prashant Mishra
Published September 20, 2022
Citation Information: J Clin Invest. 2022;132(23):e161638. https://doi.org/10.1172/JCI161638.
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Research Article Muscle biology Article has an altmetric score of 11

A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle

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Abstract

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.

Authors

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

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Figure 6

HIF1α inhibition enables maturation of Mfn2-mutant regenerating myofibers.

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HIF1α inhibition enables maturation of Mfn2-mutant regenerating myofiber...
(A) Schematic of PX-478 experiment. Tamoxifen (TMX) administration (5 consecutive days) was followed by BaCl2-induced muscle injury. At 14–28 dpi, mice were treated with PX-478 (or vehicle). (B) Representative immunofluorescence images of HIF1α (red), nuclei (DAPI, blue), and myofiber boundaries (wheat germ agglutinin [WGA], green) in 28-dpi muscle cross sections of the indicated genotype and treatment. Scale bars: 50 μm. (C) Enrichment (% of input) from H3K27me3 ChIP-qPCR experiments targeting Myh8 in 28-dpi myofibers. (D) Cross-sectional area of 28-dpi myofibers of the indicated genotype and treatment. n = 300 myofibers analyzed from 6 mice per group. (E) TA muscle weight (normalized to body weight) of the indicated genotype and treatment at 28 dpi. (F) Representative immunofluorescence images of 28-dpi muscle cross sections of the indicated genotype and treatment. Sections were stained with antibodies targeting fiber-type-specific myosin heavy chains: Myh7 (type I, purple), Myh2 (type IIa, red), Myh4 (type IIb, blue), Myh1 (type IIx, red), Myh8 (neonatal, red), and myofiber boundaries (laminin, green). Scale bar: 50 μm. Statistical significance was assessed using 2-way ANOVA (C and E) or Kruskal-Wallis (D) test with adjustments for multiple comparisons. Box-and-whisker plots indicate median (horizontal line) and interquartile ranges (bounds of the boxes) from the indicated number of biological replicates; whiskers were plotted using Tukey’s method.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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