The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism

eLife

Anirban Roy¹  Raksha Bhat¹  Meiricris Tomaz da Silva¹  Ashok Kumar¹  Takao Iwawaki²  Kyle R Bohnert³ 

[1] Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States;Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan;Kinesiology Department, St Ambrose University, Davenport, United States;

关键词: skeletal muscle;    regeneration;    ER stress;    satellite cells;    ire1 signaling;    XBP1;    Skeletal muscle regeneration;   

DOI  :  10.7554/eLife.73215

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1α or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific ablation of IRE1α dampens Notch signaling and canonical NF-κB pathway in skeletal muscle of adult mice. Finally, targeted ablation of IRE1α also reduces Notch signaling, abundance of satellite cells, and skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our experiments suggest that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.

【 授权许可】

CC BY