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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 4

Regenerating mfn2–/– myofibers are arrested at a neonatal fate.

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Regenerating mfn2–/– myofibers are arrested at a neonatal fate.
(A) Repr...
(A) Representative immunofluorescence images of muscle cross sections from mice of the indicated genotype at 14 dpi. Sections were stained with antibodies targeting fiber-type-specific myosin heavy chains, including Myh7 (type I, purple), Myh2 (type IIa, red), Myh4 (type IIb, blue), Myh1 (type IIx, red), Myh3 (embryonic, red), and Myh8 (neonatal, red). Myofiber borders were visualized with laminin staining (green). Scale bar: 50 μm. (B) Quantification of fiber types (as a percentage of total regenerating fibers) in wild-type and mfn2–/– animals at 14 and 42 dpi. (C) Levels of H3K9me3, H3K27me3, and a number of KDM family members in 14-dpi myofibers. Molecular weight markers (in kDa) are indicated. Histone 2B (H2B) and histone 3 (H3) are shown as loading controls. (D) Heatmaps representing normalized H3K9me3 ChIP-seq intensities of identified genome-wide peaks in 14-dpi myofibers of the indicated genotype, after k-means clustering. Peaks were ranked according to their ChIP-seq intensity in wild-type samples. n = 3 mice per group. (E) Heatmaps representing normalized H3K27me3 ChIP-seq intensities of identified genome-wide peaks in 14 dpi myofibers of the indicated genotype, after k-means clustering. Peaks were ranked according to their ChIP-seq intensity in wild-type samples. n = 3 mice per group. (F) Representative snapshots for H3K9me3 and H3K27me3 ChIP-seq analyses performed in 14-dpi myofibers of the indicated genotype, focusing on the myosin heavy chain locus. Increased deposition of H3K27me3 at the Myh8 gene is highlighted (red box). (G) Representative snapshots of H3K9me3 and H3K27me3 deposition at the Myh8 gene in 14-dpi myofibers of the indicated genotype. For each ChIP-seq data set, 3 biological replicates were analyzed. 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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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