miR-26a is required for skeletal muscle differentiation and regeneration in mice
miR-26a is required for skeletal muscle differentiation and regeneration in mice
复制标题
DOI：
10.1101/gad.198085.112
复制
发表时间：
2012-10-01
影响因子：
10.5
通讯作者：
Dutta, Anindya
中科院分区：
文献类型：
--
作者：
Dey, Bijan K.;Gagan, Jeffrey;Dutta, Anindya
已知在成肌细胞向肌管分化期间诱导多种microRNA。然而，动物实验没有提供明确的证据证明大多数这些microRNA在体内肌源性分化中的需要。miR-26 a在骨骼肌分化过程中被诱导，并被预测靶向一种众所周知的分化抑制剂，即转化生长因子β/骨形态发生蛋白（TGF-β/BMP）信号通路。在这里，我们表明，外源性miR-26 a促进成肌细胞的分化，而通过反义寡核苷酸或Tough-Decoys抑制miR-26 a则延迟分化。miR-26 a靶向转录因子Smad 1和Smad 4，这对TGF-β/BMP途径至关重要，这些转录因子的microRNA抗性形式的表达抑制分化。将特异性针对miR-26 a的西司他滨注射到新生小鼠中去抑制Smad表达和活性，从而抑制骨骼肌分化。此外，miR-26 a在损伤后骨骼肌再生期间被诱导。通过注射表达靶向miR-26 a的Tough-Decoy的腺相关病毒抑制胫骨前肌中的miR-26 a可防止Smad下调并延迟再生。这些发现为体内骨骼肌分化和再生需要miR-26 a提供了证据。
Multiple microRNAs are known to be induced during the differentiation of myoblasts to myotubes. Yet, experiments in animals have not provided clear evidence for the requirement of most of these microRNAs in myogenic differentiation in vivo. miR-26a is induced during skeletal muscle differentiation and is predicted to target a well-known inhibitor of differentiation, the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) signaling pathway. Here we show that exogenous miR-26a promotes differentiation of myoblasts, while inhibition of miR-26a by antisense oligonucleotides or by Tough-Decoys delays differentiation. miR-26a targets the transcription factors Smad1 and Smad4, critical for the TGF-beta/BMP pathway, and expression of microRNA-resistant forms of these transcription factors inhibits differentiation. Injection of antagomirs specific to miR-26a into neonatal mice derepressed both Smad expression and activity and consequently inhibited skeletal muscle differentiation. In addition, miR-26a is induced during skeletal muscle regeneration after injury. Inhibiting miR-26a in the tibialis anterior muscles through the injection of adeno-associated virus expressing a Tough-Decoy targeting miR-26a prevents Smad down-regulation and delays regeneration. These findings provide evidence for the requirement of miR-26a for skeletal muscle differentiation and regeneration in vivo.