A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle
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
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
View: Text | PDF
Research Article Muscle biology

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

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

×

Figure 11

Hif1α deletion accelerates myofiber maturation during muscle regeneration in response to ischemic injury.

Options: View larger image (or click on image) Download as PowerPoint
Hif1α deletion accelerates myofiber maturation during muscle regenerati...
(A) Representative immunofluorescence images of muscle cross sections from wild-type and hif1α–/– mice at the indicated time points (days post ligation, dpl). Muscle cross 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), and Myh1 (type IIx, red). Myofiber boundaries were visualized with laminin staining (green). Scale bar: 50 μm. (B) Quantification of the percentage of regenerating myofibers positive for Myh8 staining in the indicate genotypes. (C) Quantification of the percentage of regenerative myofibers of the indicated adult fiber type, in the indicated genotypes. (D) Quantification of enrichment (% of input) from H3K27me3 ChIP-qPCR experiments targeting the Myh8 gene. Experiments were performed in regenerating myofibers from animals of the indicated genotype and time point. n = 1 animal per genotype per time point. Statistical significance was assessed using 2-way ANOVA (B and D).