Inhibition of ryanodine receptor 1 in fast skeletal muscle fibers induces a fast-to-slow muscle fiber type transition

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Abstract
Skeletal muscle fiber type is regulated by innervation-induced cell signaling including calcium release mechanisms that lead to transcriptional activation of fiber type-specific genes. Avian fast pectoralis major (PM) and slow medial adductor (MA) muscles differentially control expression of the slow myosin heavy chain 2 (slow MyHC2) gene. We report here that slow MyHC2 gene expression in fast PM muscle fibers is repressed by endogenous activity of the ryanodine receptor 1 (RyR1). Inhibition of RyR1 with ryanodine led to expression of the slow MyHC2 gene in innervated PM muscle fibers in vitro. Administration of ryanodine to innervated PM muscle fibers also decreased protein kinase C (PKC) activity, the reduction of which is necessary for slow MyHC2 gene expression in both PM and MA muscle fibers. Furthermore, RyR1 inhibition increased slow MyHC2 promoter activity in innervated PM muscle fibers and enhanced transcriptional activities of nuclear factor of activated T cells (NFAT) and myocyte enhancer factor 2 (MEF2), as well as their interactions with their respective binding sites of the slow MyHC2 promoter. These results indicate that RyR1 activity in innervated fast PM muscle fibers contributes to the cell type-specific repression of slow muscle specific genes.