Maintenance of the Undifferentiated State in Myogenic Progenitor Cells by TGFβ Signaling is Smad Independent and Requires MEK Activation.

Transforming growth factor beta (TGF beta) is a pluripotent cytokine and regulates a myriad of biological processes. It has been established that TGF beta potently inhibits skeletal muscle differentiation; however, the molecular mechanism is not clearly defined. Previously, we reported that inhibition of the TGF beta canonical pathway by an inhibitory Smad, Smad7, does not reverse this effect on differentiation, suggesting that activation of receptor Smads (R-Smads) by TGF beta is not responsible for repression of myogenesis. In addition, pharmacological blockade of Smad3 activation by TGF beta did not reverse TGF beta's inhibitory effect on myogenesis. In considering other pathways, we observed that TGF beta potently activates MEK/ERK, and a pharmacological inhibitor of MEK reversed TGF beta's inhibitory effect on myogenesis, as indicated by a myogenin promoter-reporter gene, sarcomeric myosin heavy chain accumulation, and phenotypic myotube formation. Furthermore, we found that c-Jun, a known potent repressor of myogenesis, which is coincidently also a down-stream target of MEK/ERK signaling, was phosphorylated and accumulates in the nucleus in response to TGF beta activation. Taken together, these observations support a model in which TGF beta activates a MEK/ERK/c-Jun pathway to repress skeletal myogenesis, maintaining the pluripotent undifferentiated state in myogenic progenitors.