Abstract
Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remains 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 IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber- associated satellite cells. Myofiber-specific deletion of IRE1α dampens Notch signaling and canonical NF-κB pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1α reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non- autonomous manner.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The manuscript has been accepted for publication in the eLife journal. A few changes have been made that includes using Ern1 instead of Ire1 for referring mice. Ire1fl/fl mice are now referred as Ern1fl/fl mic and Ire1scko mice are referred as Ern1cKO. In addition, a few editorial changes in the text have been made as suggested by the reviewers of our manuscript.
