Regulation of skeletal muscle fiber type and slow myosin heavy chain 2 gene expression by inositol trisphosphate receptor 1

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Abstract
Innervation-dependent signaling cascades that control activation of downstream transcription factors regulate expression of skeletal muscle fiber type-specific genes. Many of the innervation-regulated signaling cascades in skeletal muscle are dependent on intracellular calcium and the mechanisms by which calcium is released from the sarcoplasmic reticulum (SR). We report that the inositol trisphosphate receptor 1 (IP3R1), responsible for calcium release from the SR as a slow wave, was more abundant in fast contracting compared to slow contracting avian muscle fibers. Furthermore, inhibition of IP3R1 activity by 2-aminoethoxydiphenylborate (2-APB) and xestospongin D induced a fiber type transition and expression of the slow myosin heavy chain 2 (slow MyHC2) gene in innervated fast muscle fibers. Activation of the slow MyHC2 promoter by IP3R1 inhibition was accompanied by a reduction in protein kinase C activity. In addition, inhibition of IP3R1 activity resulted in a reduction of nuclear factor of activated T cells (NFAT)-dependent transcription and nuclear localization, indicating that IP3R1 activity regulated NFAT transcription factor activity in skeletal muscle fibers. Myocyte enhancer factor 2 (MEF2)-dependent transcriptional activity was increased by innervation, but unaffected by IP3R1 activity. The results indicate that IP3R1 activity regulates muscle fiber type-specific gene expression in innervated muscle fibers.