Control of slow myosin heavy chain 2 gene expression by glycogen synthase kinase activity in skeletal muscle fibers

Skeletal muscle fiber type and expression of slow muscle fiber type specific genes are regulated by fiber type specific cell signaling events initiated by innervation. In avian muscle fibers, expression of the slow myosin heavy chain 2 (MyHC2) gene defines fast versus slow muscle fiber types, and its expression is dependent on the transcription factor, nuclear factor of activated T cells (NFAT). Glycogen synthase kinase 3 (GSK3) phosphorylates NFAT and inhibits its transactivating potential. We report here that expression of the slow MyHC2 gene is dependent on GSK3 activity. Inhibition of GSK3 activity by SB216763 or LiCl induced expression of the slow MyHC2 gene in non-innervated medial adductor (MA) muscle fibers and in innervated fast pectoralis major (PM) muscle fibers. Innervation of MA and PM muscle fibers did not significantly alter GSK3 activity. However, inhibition of GSK3 activity increased NFAT-mediated transcriptional activity, required for full activation of the slow MyHC2 gene, and overexpression of GSK3 reduced NFAT-mediated transcription. Inhibition of GSK3 activity was sufficient to induce slow MyHC2 gene expression in non-innervated MA muscle fibers but not in non-innervated PM muscle fibers, suggesting that fiber type specific mechanisms differentially regulate slow MyHC2 gene expression in innervated muscle fibers.