Background:Cytosolic Ca2+plays vital roles in myogenesis and muscle development. As a major Ca2+release channel of endoplasmic reticulum (ER), ryanodine receptor 1 (RyR1) key mutations are main causes of severe congenital myopathies. The role of RyR1 in myogenic differentiation has attracted intense research interest but remains unclear. Results:In the present study, both RyR1-knockdown myoblasts and CRISPR/Cas9-based RyR1-knockout myoblasts were employed to explore the role of RyR1 in myogenic differentiation, myotube formation as well as the potential mechanism of RyR1-related myopathies. We observed that RyR1 expression was dramatically increased during the late stage of myogenic differentiation, accompanied by significantly elevated cytoplasmic Ca2+concentration. Inhibition of RyR1 by siRNA-mediated knockdown or chemical inhibitor, dantrolene, significantly reduced cytosolic Ca2+and blocked multinucleated myotube formation. The elevation of cytoplasmic Ca2+concentration can effectively relieve myogenic differentiation stagnation by RyR1 inhibition, demonstrating that RyR1 modulates myogenic differentiation via regulation of Ca2+release channel. However, RyR1-knockout-induced Ca2+leakage led to the severe ER stress and excessive unfolded protein response, and drove myoblasts into apoptosis. Conclusions:Therefore, we concluded that Ca2+release mediated by dramatic increase in RyR1 expression is required for the late stage of myogenic differentiation and fusion. This study contributes to a novel understanding of the role of RyR1 in myogenic differentiation and related congenital myopathies, and provides a potential target for regulation of muscle characteristics and meat quality.

Kai Qiu;Yubo Wang;Doudou Xu;Linjuan He;Xin Zhang;Enfa Yan;Lu Wang;Jingdong Yin

State Key Laboratory of Animal Nutrition,College of Animal Science and Technology,China Agricultural University,Beijing 100193,China;Risk Assessment Laboratory of Feed Derived Factors to Animal Product Quality Safety of Ministry of Agriculture&Rural Affairs&National Engineering Research Center of Biological Feed,Institute of Feed Research,Chinese Academy of Agricultural Sciences,Beijing 100081,China

畜牧与生物技术杂志（英文版）

[1]Kai Qiu;Yubo Wang;Doudou Xu;Linjuan He;Xin Zhang;Enfa Yan;Lu Wang;Jingdong Yin-.Ryanodine receptor RyR1-mediated elevation of Ca2+concentration is required for the late stage of myogenic differentiation and fusion)[J].畜牧与生物技术杂志（英文版）,2022(04):1069-1082

Ryanodine,RyR1,Cytosolic,Ca2+plays,myotube,dantrolene,multinucleated,Ca2+leakage

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