论文部分内容阅读
Growing evidence suggests the importance of microRNAs (miRNAs) in stress signaling pathways.Transforming growth factor-β (TGF-β) is a potent cytokine that promotes the development of skeletal muscle fibrosis after acute contusion.However,how miRNAs are involved in TGF-β signaling and confer the robustness of TGF-β-induced fibrotic response remains to be fully elucidated.Here,we demonstrated that miR-146a-5p (miR-146) levels were reduced in a fibrotic mouse model after acute muscle contusion.It was also found that TGF-β treatment decreased the expression of miR-146 in vitro in a dose-and time-dependent manner.In addition,overexpression of Smad3 and Samd4,two key players in TGF-β signaling,suppressed the expression of miR-146 in muscle cells.Overexpression of miR-146 inhibited the expressions of fibrosis markers both in vitro and in vivo.Moreover,increase in the expression of miR-146 in muscle cells was able to attenuate the effect of TGF-β on the expressions of fibrosis markers.Mechanistic analysis revealed that Smad4 is a direct target of miR-146 in muscle cells.Furthermore,the anti-fibrotic effect of miR-146 could be blocked by overexpression of Smad4 in vivo.These results suggest that Smad4 is down-regulated by miR-146 in skeletal muscle.Taken together,our results indicate that the anti-fibrotic miR-146 is a component of TGF-β signaling.It is down-regulated by Smad protein,and can inhibit the expression of Smad4.Our study suggests that miR-146 might have a therapeutic potential to reduce skeletal muscle fibrosis after injury.