The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle

Abstract

ABSTRACTSkeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. Inositol requiring enzyme 1 alpha (IRE1α) is one of the arms of the unfolded protein response (UPR) that regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in adult muscle stem cells (i.e. satellite cells) of mice impairs skeletal muscle regeneration primarily through inhibiting myoblast fusion step. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits fusion of cultured myoblasts during myogenesis. Genome-wide transcriptome analysis revealed that knockdown of IRE1α or XBP1 deregulates the gene expression of molecules involved in the regulation of myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including Myomaker (Mymk) during myogenic differentiation. Our study demonstrates that spliced XBP1 (sXBP1) transcription factor binds to the promoter region ofMymkgene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Finally, our results show that inducible deletion ofIRE1α in satellite cells inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation in the gene expression of profusion molecules.Significance StatementMyoblast fusion is an essential step for regeneration and post-natal growth of skeletal muscle. We demonstrate that the activation of the IRE1α/XBP1 arm of the unfolded protein response induces myoblast fusion through augmenting the gene expression of multiple profusion molecules, including myomaker. This study has identified a novel signaling axis that link ER stress-induced non-myogenic signaling pathway to myoblast fusion. Augmenting the activity of IRE1α/XBP1 pathway could be a potential therapeutic strategy for various muscle degenerative diseases.