The IRE1α/XBP1 signaling 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. IRE1 alpha, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1 alpha in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1 alpha or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1 alpha or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1 alpha-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk). Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1 alpha-knockdown cultures rescues fusion defects. Inducible deletion of IRE1 alpha in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1 alpha promotes myoblast fusion through sXBP1-mediated up-regulation of the gene expression of multiple profusion molecules, including myomaker. The IRE1 alpha/XBP1 arm of the unfolded protein response promotes myoblast fusion during skeletal muscle regeneration and overload-induced myofiber hypertrophy.IRE1 alpha signaling in satellite cells promotes skeletal muscle regeneration in adult mice.Silencing of IRE1 alpha or XBP1 inhibits myoblast fusion without affecting their differentiation.The IRE alpha/XBP1 signaling induces the gene expression of multiple proteins involved in myoblast fusion, including myomaker.Satellite cell-specific ablation of IRE1 alpha inhibits muscle hypertrophy in response to functional overload. The IRE1 alpha/XBP1 arm of the unfolded protein response promotes myoblast fusion during skeletal muscle regeneration and overload-induced myofiber hypertrophy.