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Insulin-Like Growth Factor-Induced Transcriptional Activity of the Skeletal -Actin Gene Is Regulated by Signaling Mechanisms Linked to Voltage-Gated Calcium Channels during Myoblast Differentiation

Department of Biomedical Sciences (E.E.S., D.K.B., F.W.B.), Department of Medical Pharmacology and Physiology (F.W.B.), and Dalton Cardiovascular Research Center (D.K.B., F.W.B.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Frank W. Booth, Ph. D., University of Missouri, Department of Biomedical Sciences, E102 Veterinary Medical Building, 1600 East Rollins Road, Columbia, Missouri 65211. E-mail: boothf{at}missouri.edu.

IGF-I activates signaling pathways that increase the expression of muscle-specific genes in differentiating myoblasts. Induction of skeletal -actin expression occurs during differentiation through unknown mechanisms. The purpose of this investigation was to examine the mechanisms that IGF-I uses to induce skeletal -actin gene expression in C2C12 myoblasts. IGF-I increased skeletal -actin promoter activity by 107% compared with the control condition. Ni⁺ [T-type voltage-gated Ca²⁺ channel (VGCC) inhibitor] reduced basal-induced activation of the skeletal -actin promoter by approximately 84%, and nifedipine (L-type VGCC inhibitor) inhibited IGF-I-induced activation of the skeletal -actin promoter by 29–48%. IGF-I failed to increase skeletal -actin promoter activity in differentiating dysgenic (lack functional L-type VGCC) myoblasts; 30 mM K⁺ and 30 mM K⁺+IGF-I increased skeletal -actin promoter activity by 162% and 76% compared with non-IGF-I or IGF-I-only conditions, respectively. IGF-I increased calcineurin activity, which was inhibited by cyclosporine A. Further, cyclosporine A inhibited K⁺+IGF-I-induced activation of the skeletal -actin promoter. Constitutively active calcineurin increased skeletal -actin promoter activity by 154% and rescued the nifedipine-induced inhibition of L-type VGCC but failed to rescue the Ni⁺-inhibition of T-type VGCC. IGF-I-induced nuclear factor of activated T-cells transcriptional activity was not inhibited by nifedipine or Ni⁺. IGF-I failed to increase serum response factor transcriptional activity; however, serum response factor activity was reduced in the presence of Ni⁺. These data suggest that IGF-I-induced activation of the skeletal -actin promoter is regulated by the L-type VGCC and calcineurin but independent of nuclear factor of activated T-cell transcriptional activity as C2C12 myoblasts differentiate into myotubes.

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