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Sema4C is a member of transmembrane semaphorin proteins which regulate axonal guidance in the developing nervous system.The expression of Sema4C was dramatically induced not only during differentiation of C2C12 mouse myoblasts,but also during injury-induced skeletal muscle regeneration.C2C12 cells stably or transiently expressing Sema4C both showed increased myogenic differentiation reflected by accelerated myotube formation and expression of muscle-specific proteins.Overexpression of Sema4C elicited p38 phosphorylation directly,and the effects of Sema4C during myogenic differentiation could be abolished by the p38a-specific inhibitor SB203580.Knockdown of Sema4C by siRNA transfection during C2C12 myoblasts differentiation could suppress the phosphorylation of p38 followed by dramatically diminished myotube formation.Sema4C could activate the myogenin promoter during myogenic differentiation.