Published on Thu Aug 19 2021

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

Roy, A., Tomaz da Silva, M., Bhat, R., Bohnert, K. R., Iwawaki, T., Kumar, A.

The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. The role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1a-XBP1 pathway

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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 remain less understood. In the present study, we demonstrate that IRE1a-XBP1 pathway is activated in skeletal muscle of mice upon injury. Myofiber-specific deletion of IRE1a or XBP1 in mice diminishes skeletal muscle regeneration accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1a reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific deletion of IRE1alpha dampens Notch signaling and canonical NF-kappa B (NF-kB)pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1alpha reduces skeletal muscle regeneration in the mdx model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.