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 9

Loss of IRE1α exacerbates the dystrophic phenotypes in mdx mice.

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Loss of IRE1α exacerbates the dystrophic phenotypes in mdx mice. (A) Qua...
(A) Quantitative RT-PCR analysis of Xbp1 mRNA splicing and the mRNA abundance of Mstn in TA muscles from male mdx/Ern1fl/fl and mdx/Ern1fl/fl Myod1-Cre mice at 6 weeks of age (n = 5–6 mice per genotype). (B) ELISA analysis of serum myostatin levels (n = 5–6 mice per genotype). (C) Immunoblot analysis of TA muscle lysates using the indicated antibodies. (D) Averaged p-Smad3/Smad3 and eMyHC/tubulin ratios after normalization to the value in mdx muscle (n = 5–6 mice per genotype). (E and F) Representative pictures (E) and weight (F) of gastrocnemius (Gas) and TA muscles from mdx/Ern1fl/fl and mdx/Ern1fl/fl Myod1-Cre mice at 6 weeks of age (n = 5–6 mice per genotype). (G and H) Representative images of H&E staining of Gas and TA muscles (G) and laminin (green) immunostaining of Gas and TA muscles (H) (n = 5 mice per genotype). (I) Percentage of myofibers in the indicated cross-sectional areas of TA muscle. Quantification was conducted by ImageJ from 500 myofibers of the TA muscle from each mouse (n = 5 mice per genotype). (J and K) Analysis of Evans blue dye uptake of Gas and TA muscles (n = 5 mice per genotype). (J) Representative images of Gas and TA muscles. (K) Representative fluorescent micrographs of muscle sections. (L and M) Serum creatine kinase (CK) activity (L) and mean running time and distance on a motorized treadmill (M) for mice of the indicated genotypes at 6 weeks of age (n = 5 mice per genotype). All data are shown as mean ± SEM. Significance was calculated by unpaired 2-tailed Student’s t test (A, B, D, and F), 2-way ANOVA (I), or 1-way ANOVA (L and M) with Bonferroni’s multiple-comparison test. *P < 0.05, **P < 0.01, ***P < 0.001. Scale bars: 100 μm.