Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States.
Kinesiology Department, St Ambrose University, Davenport, United States.
Elife. 2021 Nov 23;10:e73215. doi: 10.7554/eLife.73215.
Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1α or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific ablation of IRE1α dampens Notch signaling and canonical NF-κB pathway in skeletal muscle of adult mice. Finally, targeted ablation of IRE1α also reduces Notch signaling, abundance of satellite cells, and skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our experiments suggest that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.
骨骼肌再生受多种信号通路协调激活的调控。未折叠蛋白反应（UPR）是一种主要的机制，可检测内质网中蛋白质折叠的应激，并减轻其压力。然而，UPR 的各个分支在骨骼肌再生中的作用仍知之甚少。在本研究中，我们证明了在受到损伤后，IRE1α（也称为 ERN1）及其下游靶点 XBP1 在小鼠骨骼肌中被激活。在小鼠中肌纤维特异性敲除 IRE1α 或 XBP1 会减少骨骼肌再生，伴随着卫星细胞数量减少。肌纤维外植体的体外培养表明，IRE1α 的敲除会降低肌纤维相关卫星细胞的增殖能力。在成年小鼠的骨骼肌中，IRE1α 的肌纤维特异性敲除会抑制 Notch 信号和经典 NF-κB 通路。最后，IRE1α 的靶向敲除也会减少 Notch 信号、卫星细胞的丰度以及 Duchenne 肌营养不良症模型 mdx 小鼠的骨骼肌再生。总的来说，我们的实验表明，IRE1α 介导的信号通过以非细胞自主的方式增强卫星细胞的增殖来促进肌肉再生。
