The Regulatory Mechanism Of IRE1? In Muscle Differentiation And Regeneration

The endoplasmic reticulum is an important membranous reticulum organelle in eukaryotic cells,which controls the synthesis,folding,secretion and transport of nearly one-third of the cell's proteome.In the endoplasmic reticulum,secreted and transmembrane proteins are folded into their native conformations and undergo posttranslational modifications,which are critical for their proper structure and normal function.However,when the demand for protein folding increases or the unfolded and misfolded proteins accumulate in the ER lumen,ER stress will be triggered and the unfolded protein response will be activated.Activation of the UPR signaling pathways are mediated by the stress sensors IRE1,PERK,and ATF6,which relieve ER stress and restore cellular homeostasis by reducing cellular synthetic loading and increasing the protein synthesis capacity of the ER.Skeletal muscle is a highly plastic tissue that exhibits remarkable muscle fiber regeneration ability when subjected to physiological or pathological injury.Muscle repair is a delicately coordinated process involving satellite cell activation,differentiation,and muscle fiber remodeling.During the final stages of muscle repairing,myotubes undergo hypertrophic remodeling,with the myonuclei moving around the muscle fibers,producing mature muscle fibers that restore their ability to contract.The muscle regeneration process is regulated by multiple signaling pathways,including the cooperative activation of transcriptional regulators Myf5,Myo D,and Mygenin,and the expression of the myosin heavy chain(My HC)genes.Impaired muscle regeneration and growth can lead to muscle wasting or dystrophy,leading to skeletal muscle-related diseases.Myostatin is a secreted factor that negatively regulates myogenic differentiation,and is also involved in inhibiting the proliferation and differentiation of muscle stem cells and delaying muscle regeneration.As a highly conserved transmembrane protein located on the endoplasmic reticulum,IRE1? mediates an important signaling pathway of the UPR,and is involved in the regulation of cell proliferation,metabolism,inflammation and apoptosis.In our study,it was found that the endoribonuclease activity of IRE1? is involved in the regulation of myoblast differentiation into myotubes and regeneration after muscle atrophy.Next,we constructed an Ern1-m KO mouse model and demonstrated that IRE1? promotes myoblast differentiation in an RNase-dependent manner.Then by constructing Mstn-KO C2C12 cells,we demonstrated the negative regulation of IRE1? on myostatin expression at the cellular and molecular levels.Finally,we used the mdx mouse model to demonstrate that at the physiological level the IRE1? plays a role in promoting the regeneration of dystrophic muscle by inhibiting the expression of myostatin.Our results reveal the critical role of the RNase activity of IRE1? in promoting muscle regeneration and differentiation,which may provide a new target for the treatment of skeletal muscle-related diseases.