ERK1/2 is required for myoblast proliferation but is dispensable for muscle gene expression and cell fusion

Skeletal muscle satellite cells, which are found between the muscle fiber a nd the basal lamina, remain quiescent and undifferentiated unless stimulate d to remodel skeletal muscle or repair injured skeletal muscle tissue. Quie scent satellite cells express c-met and fibroblast growth factor receptors (FGFR) 1 and 4, suggesting these receptors are involved in maintaining the undifferentiated quiescent state or involved in satellite cell activation. Although the signaling pathways involved are poorly understood, the mitogen activated protein kinase (MAPK) cascade has been implicated in the regulat ion of skeletal muscle growth and differentiation by FGFs. In this study, w e investigated if activation of the Raf-MKK1/2-ERK1/2 signaling cascade pla ys a role in FGF-dependent repression of differentiation and proliferation of MM14 cells, a skeletal muscle satellite cell line. Inactivation of the R af-MKK1/2-ERK1/2 pathway in myoblasts through the overexpression of dominan t negative mutants of Raf-1 blocks ERK1/2 activity and prevents myoblast pr oliferation. Additionally, inhibition of MKK1/2 by treatment with pharmacol ogical inhibitors also blocks FGF-mediated stimulation of ERK1/2 and blocks the G1 to S phase transition of myoblasts. Unexpectedly, we found that ina ctivation of the Raf-ERK pathway does not activate a muscle reporter, nor d oes inactivation of this pathway promote myogenic differentiation. We concl ude that FGF-stimulated ERK1/2 signaling is required during the G1 phase of the cell cycle for commitment of myoblasts to DNA synthesis but is not req uired for mitosis once cells have entered the S-phase. Moreover, ERK1/2 sig naling is not required either to repress differentiation, to promote skelet al muscle gene expression, or to promote myoblast fusion. J. Cell. Physiol. 786:104-115, 2001. (C) 2001 Wiley-Liss, Inc.