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IRE1α regulates skeletal muscle regeneration through myostatin mRNA decay
Shengqi He, … , Zhenji Gan, Yong Liu
Shengqi He, … , Zhenji Gan, Yong Liu
Published July 20, 2021
Citation Information: J Clin Invest. 2021;131(17):e143737. https://doi.org/10.1172/JCI143737.
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Research Article Muscle biology

IRE1α regulates skeletal muscle regeneration through myostatin mRNA decay

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Abstract

Skeletal muscle can undergo a regenerative process in response to injury or disease to preserve muscle mass and function, which are critically influenced by cellular stress responses. Inositol-requiring enzyme 1 (IRE1) is an ancient endoplasmic reticulum stress sensor and mediates a key branch of the unfolded protein response. In mammals, IRE1α is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1α serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1α was activated during injury-induced muscle regeneration, and muscle-specific IRE1α ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1α acts to sustain both differentiation in myoblasts and hypertrophy in myotubes through regulated IRE1-dependent decay (RIDD) of mRNA encoding myostatin, a key negative regulator of muscle repair and growth. Furthermore, in the mouse model of Duchenne muscular dystrophy, loss of muscle IRE1α resulted in augmented myostatin signaling and exacerbated the dystrophic phenotypes. These results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering insight into potential therapeutic strategies for muscle loss diseases.

Authors

Shengqi He, Tingting Fu, Yue Yu, Qinhao Liang, Luyao Li, Jing Liu, Xuan Zhang, Qian Zhou, Qiqi Guo, Dengqiu Xu, Yong Chen, Xiaolong Wang, Yulin Chen, Jianmiao Liu, Zhenji Gan, Yong Liu

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Figure 6

Inhibition in vivo of myostatin signaling rescues the impairment of muscle regeneration resulting from IRE1α deficiency.

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Inhibition in vivo of myostatin signaling rescues the impairment of musc...
Male Ern1fl/fl or Ern1fl/fl Myod1-Cre mice were injected intraperitoneally on postnatal day 3 (P3) and P6 with adeno-associated virus 2/9 (AAV2/9) expressing GFP (AAV-GFP) or MyoPPT (AAV-MyoPPT). TA muscles of indicated mice were injected with PBS or CTX at 7 weeks of age and analyzed at 8 days after injection. (A and B) Quantitative RT-PCR analysis of the mRNA abundance of MyoPPT (A) and Xbp1 mRNA splicing (B) in PBS-treated uninjured TA muscles (n = 6 mice per group). (C) Body weight of mice of the indicated groups. (D) Weight of PBS-treated uninjured TA muscles. (E) Weight of CTX-injured TA muscles from mice of the indicated groups (n = 5–7 mice per group). (F and G) Representative H&E staining (F) and laminin (green) and eMyHC (red) immunostaining (G) of injured TA muscles (n = 5 mice per group). (H) Percentage of regenerated myofibers in the indicated cross-sectional areas of TA muscles. Myofibers containing centralized nuclei were quantified by ImageJ from 500 myofibers in each mouse (n = 5 mice per group). (I) Quantification of the percentage of eMyHC+ myofibers within laminin staining (n = 5 mice per group). All data are presented as mean ± SEM. Significance was calculated by 2-way ANOVA with Bonferroni’s multiple-comparison test. *P < 0.05, **P < 0.01, ***P < 0.001 vs. Ern1fl/fl + AAV-GFP. #P < 0.05, ###P < 0.001 vs. Ern1fl/fl Myod1-Cre + AAV-GFP. Scale bars: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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