miR-146a-5p acts as a negative regulator of TGF-β signaling in skeletal muscle after acute contusion
miR-146a-5p acts as a negative regulator of TGF-β signaling in skeletal muscle after acute contusion
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DOI：
10.1093/abbs/gmx052
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发表时间：
2017-07-01
影响因子：
3.7
通讯作者：
Ying, Hao
中科院分区：
文献类型：
--
作者：
Sun, Yaying;Li, Yan;Ying, Hao
越来越多的证据表明microRNAs （miRNAs）在胁迫信号通路中的重要性。转化生长因子- β (tgf - β)是一种促进急性挫伤后骨骼肌纤维化发展的有效细胞因子。然而，mirna如何参与tgf - β信号传导并赋予tgf - β诱导的纤维化反应的稳健性仍有待充分阐明。在这里，我们证明了急性肌肉挫伤后纤维化小鼠模型中miR-146a-5p （miR-146）水平降低。研究还发现，tgf - β治疗在体外以剂量和时间依赖的方式降低miR-146的表达。此外，tgf - β信号传导的两个关键参与者Smad3和Samd4的过表达抑制了miR-146在肌肉细胞中的表达。在体外和体内，过表达miR-146抑制了纤维化标志物的表达。此外，肌细胞中miR-146表达的增加能够减弱tgf - β对纤维化标志物表达的影响。机制分析显示Smad4是肌细胞中miR-146的直接靶点。此外，miR-146的抗纤维化作用可通过体内Smad4的过表达而被阻断。这些结果表明Smad4在骨骼肌中被miR-146下调。综上所述，我们的研究结果表明，抗纤维化miR-146是tgf - β信号的一个组成部分。它被Smad蛋白下调，可以抑制Smad4的表达。我们的研究表明，miR-146可能具有减少损伤后骨骼肌纤维化的治疗潜力。
Growing evidence suggests the importance of microRNAs (miRNAs) in stress signaling pathways. Transforming growth factor-beta (TGF-beta) is a potent cytokine that promotes the development of skeletal muscle fibrosis after acute contusion. However, how miRNAs are involved in TGF-beta signaling and confer the robustness of TGF-beta-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-beta 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-beta 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-beta 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-beta 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.