Critical proliferation-independent window for basic fibroblast growth factor repression of myogenesis via the p42/p44 MAPK signaling pathway

In many cell types including myoblasts, growth factors control proliferatio n and differentiation, in part, via the mitogen-activated protein kinase (M APK) pathway (also known as the extracellular regulated kinase (Erk) pathwa y). In C2C12 myoblast cells, insulin-like growth factor-1 and basic fibrobl ast growth factor (bFGF) activate MAPK/Erk, and both growth factors promote myoblast proliferation. However, these factors have opposing roles with re spect to differentiation; insulin-like growth factor-1 enhances muscle cell differentiation, whereas bFGF inhibits the expression of the muscle specif ic transcription factors MyoD and myogenin, Cells treated with bFGF and PD9 8059, a specific inhibitor of the MAPK pathway, show enhanced expression of the muscle-specific transcription factors MyoD and myogenin as compared wi th cells not exposed to this inhibitor. Inhibiting MAPK activity also enhan ces myoblast fusion and the expression of the late differentiation marker m yosin heavy chain. Basic FGF mediated repression of muscle-specific genes d oes not result from continued cell proliferation, since bFGF-treated cells progress through only one round of cell division, We have identified a crit ical boundary 16 to 20 h after plating during which bFGF induced MAPK activ ity is able to repress myogenic gene expression and differentiation. Thus, the targets of MAPK that regulate myogenesis are functional at this time an d their identification is in progress.