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

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 5

Myostatin ablation reverses the effect of IRE1α deficiency on muscle cell differentiation and growth.

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Myostatin ablation reverses the effect of IRE1α deficiency on muscle cel...
WT and Mstn-KO C2C12 myoblast cells were infected for 24 hours with Sh-Con or Sh-Ern1 adenoviruses and then differentiated for 3–4 days in myogenic medium. (A–C) Representative images of MyHC immunostaining (A), and quantification of the fusion index (B) and myotube diameters (C) (n = 4 independent experiments). (D) ELISA analysis of myostatin protein in culture medium (n = 3 independent experiments). (E and F) Immunoblot analysis of the indicated proteins (E), and quantification of averaged MSTN/tubulin, MyoG/tubulin, MyHC/tubulin, and p-Smad3/Smad3 levels (F) (n = 3 independent experiments). (G) Quantitative RT-PCR analysis of Xbp1 mRNA splicing and the mRNA abundance of the indicated genes (n = 4 independent experiments). All results represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA with Bonferroni’s multiple-comparison test. Ud, undetectable. Scale bars: 100 μm.