IRE1 alpha regulates skeletal muscle regeneration through myostatin mRNA decay

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.