Inhibition of ryanodine receptor 1 in fast skeletal muscle fibers induces a fast-to-slow muscle fiber type transition
Inhibition of ryanodine receptor 1 in fast skeletal muscle fibers induces a fast-to-slow muscle fiber type transition
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DOI：
10.1242/jcs.01543
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发表时间：
2004-12-01
影响因子：
4
通讯作者：
DiMario, JX
中科院分区：
文献类型：
--
作者：
Jordan, T;Jiang, HB;DiMario, JX
骨骼肌纤维类型受神经支配诱导的细胞信号传导调节，包括导致纤维类型特异性基因转录激活的钙释放机制。鸟类快胸大肌（PM）和慢内侧内收肌（MA）肌肉差异控制慢肌球蛋白重链2（慢MyHC2）基因的表达。我们在这里报告说，慢MyHC2基因表达在快速PM肌纤维的内源性活性的ryanodine受体1（RyR1）的抑制。RyR1与ryanodine抑制导致表达的慢MyHC2基因在神经支配的PM肌纤维在体外。给受神经支配的PM肌纤维施用ryanodine也降低了蛋白激酶C（PKC）活性，其减少对于PM和MA肌纤维中的缓慢MyHC 2基因表达是必要的。此外，RyR1抑制增加了慢MyHC2启动子在神经支配的PM肌纤维的活性，并增强了活化T细胞核因子（NFAT）和肌细胞增强因子2（MEF2）的转录活性，以及它们与慢MyHC2启动子各自结合位点的相互作用。这些结果表明，RyR1活性在受神经支配的快PM肌纤维有助于细胞类型特异性抑制慢肌特异性基因。
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.