PDF(Pubmed)
Abstract：
Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. IRE1α, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-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 IRE1α-knockdown cultures rescues fusion defects. Inducible deletion of IRE1α in satellite cells also 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 the gene expression of multiple profusion molecules, including myomaker.
摘要：
骨骼肌再生涉及调节增殖的信号网络，分化,肌肉前体细胞与受损的肌纤维融合。IRE1α,展开的蛋白质反应的一个分支，调节响应ER应激的细胞蛋白质停滞。这里,我们证明，小鼠卫星细胞中IRE1α的诱导性缺失通过抑制成肌细胞融合来损害骨骼肌再生。击倒IRE1α或其下游靶标，X-box蛋白1（XBP1），也抑制成肌细胞在成肌期融合。转录组分析显示IRE1α或XBP1的敲低失调参与成肌细胞融合的分子的基因表达。IRE1α-XBP1轴介导多个profusion分子的基因表达，包括Myomaker(Mymk)。剪接的XBP1（sXBP1）转录因子在肌生成过程中与Mymk基因的启动子结合。IRE1α敲低培养物中Myomaker的过表达可挽救融合缺陷。卫星细胞中IRE1α的可诱导缺失也会抑制成肌细胞融合和肌纤维肥大，以响应功能超负荷。总的来说，我们的研究表明，IRE1α促进成肌细胞融合通过sXBP1介导的基因表达上调的多个profusion分子，包括Myomaker.
