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

Skeletal 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 mainly through inhibiting myoblast fusion. 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 dysregulates the gene expression of multiple molecules involved in the regulation of myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of Myomaker ( Mymk ), a critical regulator of myoblast fusion. Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of Myomaker in IRE1α-knockdown cultures rescues fusion defects. Finally, our results show that inducible deletion of IRE1 α 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 of gene expression of Myomaker protein. ### Competing Interest Statement The authors have declared no competing interest.