Smad7 Promotes and Enhances Skeletal Muscle Differentiation

Abstract

Transforming growth factor ␤1 (TGF-␤1) and myostatin signaling, mediated by the same Smad downstream effectors, potently repress skeletal muscle cell differentiation. Smad7 inhibits these cytokine signaling pathways. The role of Smad7 during skeletal muscle cell differentiation was assessed. In these studies, we document that increased expression of Smad7 abrogates myostatin-but not TGF-␤1-mediated repression of myogenesis. Further, constitutive expression of exogenous Smad7 potently enhanced skeletal muscle differentiation and cellular hypertrophy. Conversely, targeting of endogenous Smad7 by small interfering RNA inhibited C2C12 muscle cell differentiation, indicating an essential role for Smad7 during myogenesis. Congruent with a role for Smad7 in myogenesis, we observed that the muscle regulatory factor (MyoD) binds to and transactivates the Smad7 proximal promoter region. Finally, we document that Smad7 directly interacts with MyoD and enhances MyoD transcriptional activity. Thus, Smad7 cooperates with MyoD, creating a positive loop to induce Smad7 expression and to promote MyoD driven myogenesis. Taken together, these data implicate Smad7 as a fundamental regulator of differentiation in skeletal muscle cells.

Myostatin antisense RNA-mediated muscle growth in normal and cancer cachexia mice

“…16,17 More recently, there have been reports revealing some direct action of myostatin on the myogenic factors. 18,19 In the current study, we did show that the inhibition of myostatin expression by antisense RNAs elevated the level of MyoD expression at the mRNA level in vivo. Thus, our results elucidate a possible mechanism for targeting the myostatin gene for potential treatment of the muscle wasting diseases and provide further evidence that myostatin regulates the muscle growth through the MyoD pathways.…”

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

“…These processes were associated with the upregulation of the expression of Smad3 and 4, and the phosphorylation of Smad2 and 3, as expected from a member of the TGF-b family that signals through this pathway (Zhu et al 2004, Kollias et al 2006). An antifibrotic process was simultaneously elicited, as evidenced by the stimulation of the expression of a) the myostatin activity inhibitor, follistatin (Hill et al 2002, Amthor et al 2004, Kocamis et al 2004, b) a Smad signaling inhibitor, Smad7 (Forbes et al 2006), and c) a collagen breakdown inducer, matrix metalloproteinase 8 (MMP-8;Siller-Lopez et al 2004).…”

“…This is likely to occur via the Smad pathway, since myostatin signals through Smad2-4, and phosphorylates Smad3 (Zhu et al 2004). In addition, it triggers a feedback compensatory mechanism through the inhibitory Smad7 that inactivates myostatin promoter, and counteracts myostatin and TGF-b action (Zhu et al 2004, Forbes et al 2006, Kollias et al 2006. In turn, Smad2-4 upregulate myostatin expression by activating its promoter (Zhu et al 2004).…”

Coco is a dual-activity modulator of TGF-β signaling

“…We first determined the effects of Coco on the differentiation of C2C12 cells to myoblasts, a process that is inhibited by TGFβ1 (Kollias et al, 2006). We found that C2C12 cells transfected with a Coco siRNA have a twofold higher rate of myoblast differentiation, as determined by myogenin immunostaining, compared with cells transfected with a control siRNA (Fig.…”