Muscle early genes regulation Depolarization induced slow calcium transients activate early genes in skeletal muscle cells

The signaling mechanisms by which skeletal muscle electrical activity leads to changes in gene expression remain largely undefined. We have reported that myotubes depolarization induces calcium signals in cytosol and nucleus via inositol 1,4,5-trisphosphate (IP3) and phosphorylation of both ERKs 1/2 and cAMP-response element-binding protein (CREB). We now describe the calcium dependence of P-CREB and P-ERKs induction and of the increases in early genes c-fos, c-jun and egr-1 mRNA. Increased phosphorylation and early genes activation were maintained in the absence of extracellular calcium, while the increase in intracellular calcium induced by caffeine could mimic the depolarization stimulus. Depolarization performed either in the presence of the IP3 inhibitors 2-aminoethoxydiphenyl borate (2-APB) or xestospongin C or on cells loaded with BAPTA-AM, in which slow calcium signals were abolished, resulted in decreased activation of the early genes examined. Both early genes activation and CREB phosphorylation were inhibited by ERKs phosphorylation blockade. These data suggest a role for calcium in the transcription-related events that follow membrane depolarization in muscle cells.