IRE1α regulates skeletal muscle regeneration through myostatin mRNA decay
IRE1α regulates skeletal muscle regeneration through myostatin mRNA decay
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IRE1α 通过肌肉生长抑制素 mRNA 衰减调节骨骼肌再生
DOI：
10.1172/jci143737
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发表时间：
2021-01-01
影响因子：
15.9
通讯作者：
Liu, Yong
中科院分区：
文献类型：
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作者：
He, Shengqi;Fu, Tingting;Liu, Yong
骨骼肌在受到损伤或疾病的影响时，可以经历再生过程，以保持肌肉质量和功能，这是受细胞应激反应严重影响的。肌醇要求酶1 （IRE1）是一种古老的内质网应激传感器，介导了未折叠蛋白反应的一个关键分支。在哺乳动物中，IRE1 α参与组织损伤和再生过程中应激反应的稳态控制。在这里，我们发现IRE1 α在骨骼肌损伤和肌肉萎缩后的再生中起肌源性调节作用。我们在小鼠中发现，IRE1 α在损伤诱导的肌肉再生过程中被激活，肌肉特异性IRE1 α消融导致心脏毒素诱导的损伤后再生受损。肌细胞的功能增益和功能丧失研究表明，IRE1 α通过调节编码肌肉生长抑制素的mRNA的IRE1依赖性衰变（RIDD）来维持成肌细胞的分化和肌管的肥大，肌生长抑制素是肌肉修复和生长的关键负调节因子。此外，在杜氏肌营养不良小鼠模型中，肌肉IRE1 α的缺失导致肌肉生长抑制素信号增强，并加剧了营养不良表型。这些结果揭示了IRE1 α的RIDD输出在肌肉再生中的关键作用，为肌肉损失疾病的潜在治疗策略提供了见解。
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, IRE1 alpha is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1 alpha serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1 alpha was activated during injury-induced muscle regeneration, and muscle-specific IRE1 alpha ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1 alpha 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 IRE1 alpha resulted in augmented myostatin signaling and exacerbated the dystrophic phenotypes. These results reveal a pivotal role for the RIDD output of IRE1 alpha in muscle regeneration, offering insight into potential therapeutic strategies for muscle loss diseases.