SMAD2 Promotes Myogenin Expression and Terminal Myogenic Differentiation

ABSTRACT SMAD2 is a transcription factor whose activity is regulated by members of the Transforming Growth Factor beta (TGFβ) superfamily. While activation of SMAD2 and SMAD3 downstream of TGFβ or myostatin signaling is known to inhibit myogenesis, we find that SMAD2 in the absence of TGFβ signaling promotes terminal myogenic differentiation. We find that during myogenic differentiation, SMAD2 expression is induced. Knockout of SMAD2 expression in primary myoblasts did not affect the efficiency of myogenic differentiation but produced smaller myotubes with reduced expression of the terminal differentiation marker myogenin. Conversely, overexpression of SMAD2 stimulated myogenin expression, and enhanced both differentiation and fusion, and these effects were independent of classical activation by the TGFβ receptor complex. Loss of Smad2 in muscle satellite cells in vivo resulted in decreased muscle fiber caliber and impaired regeneration after acute injury. Taken together, we demonstrate that SMAD2 is an important positive regulator of myogenic differentiation, in part through the regulation of Myog . SUMMARY STATEMENT TGFβ and SMAD2 are normally associated with inhibition of myogenesis. Our work identifies a pro-myogenic role for SMAD2 during terminal myogenic differentiation, through regulation of Myog and Klf4 expression.