Abstract
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.
Highlights
Skeletal muscle, the most abundant tissue of the body, has remarkable regenerative capacity mainly due to its resident muscle stem cells, known as satellite cells
Results showed that the levels of phosphorylated IRE1α were significantly increased in tibialis anterior (TA) muscle at day 5 post-injury compared to contralateral control muscle
The levels of spliced XBP1 protein were found to be considerably increased in injured TA muscle of mice suggesting activation of the IRE1α/XBP1 pathway in injured muscle (Figure 1A)
Summary
The most abundant tissue of the body, has remarkable regenerative capacity mainly due to its resident muscle stem cells, known as satellite cells. Because regeneration of injured skeletal muscle involves a huge increase in demand for synthesis, processing, and secretion of multiple growth factors and signaling proteins and synthesis of an entirely new set of contractile, cytoskeletal, and membrane proteins, the activation of UPR may be a physiological response to ensure that cells participating in regeneration continue to function efficiently during these increased demands. Recent studies have suggested that PERK arm of the UPR is required for maintaining satellite cells in a quiescent state in skeletal muscle of adult mice. Genetic inducible ablation of PERK in satellite cells inhibits skeletal muscle regeneration in adult mice (Xiong et al, 2017; Zismanov et al, 2016). The role and the mechanisms by which the IRE1α/XBP1 signaling in myofiber regulates skeletal muscle regeneration in adult mice remain poorly understood. Our experiments demonstrate that genetic ablation of IRE1α exacerbates myopathy and reduces the number of satellite cells in skeletal muscle of dystrophin-deficient mdx (a model of DMD) mice
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