p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation - Participation of the MEF2C transcription factor

Differentiation of muscle cells is regulated by extracellular growth factor s that transmit largely unknown signals into the cells. Some of these growt h factors induce mitogen-activated protein kinase (MAPK) cascades within mu scle cells, In this work we show that the kinase activity of p38 MAPK is in duced early during terminal differentiation of L8 cells. Addition of a spec ific p38 inhibitor SE 203580 to myoblasts blocked their fusion to multinucl eated myotubes and prevented the expression of MyoD and MEF2 family members and myosin light chain 2, The expression of MKK6, a direct activator of p3 8, or of p38 itself enhanced the activity of MyoD in converting 10T1/2 fibr oblasts to muscle, whereas treatment with SE 203580 inhibited MyoD, Several lines of evidence suggesting that the involvement of p38 in MyoD activity is mediated via its co-activator MEF2C, a known substrate of p38, are prese nted. In these experiments we show that MEF2C protein and MEF2-binding site s are necessary for the p38 MAPK pathway to regulate the transcription of m uscle creatine kinase reporter gene. Our results indicate that the p38 MAPK pathway promotes skeletal muscle differentiation at least in part via acti vation of MEF2C.