Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis
Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis
复制标题
DOI：
10.1242/jcs.119966
复制
发表时间：
2013-06-15
影响因子：
4
通讯作者：
Kunkel, Louis M.
中科院分区：
文献类型：
--
作者：
Motohashi, Norio;Alexander, Matthew S.;Kunkel, Louis M.
骨骼肌在受伤后具有很强的再生能力，这在很大程度上归因于卫星细胞。卫星细胞是位于肌纤维基底层下的骨骼肌干细胞，是骨骼肌生长和再生的主要细胞来源。microRNAs（miRNAs）通过靶向包含单个或多个信号通路的多个mRNA在调节几种细胞过程中发挥关键作用。一些miRNA已经显示出调节卫星细胞活性，例如miRNA-489，其功能是维持卫星细胞处于静止状态。虽然已经鉴定出肌肉特异性的miRNAs，但是许多由miRNAs调节的调节肌发生的分子机制仍然未知。在这项研究中，我们发现miR-128 a在大脑和骨骼肌中高度表达，并在成肌细胞分化过程中增加。MiR-128 a在mRNA和蛋白质水平上调节胰岛素信号转导的靶基因，包括Insr（胰岛素受体）、Irs 1（胰岛素受体底物1）和Pik 3r 1（磷脂酰肌醇3-激酶调节1）。成肌细胞中miR-128 a的过表达通过靶向IRS 1抑制细胞增殖。相比之下，抑制miR-128 a在体外和体内诱导肌管成熟和肌纤维肥大。此外，我们的研究结果表明，miR-128 a的表达水平是负控制的肿瘤坏死因子α（TNF-α）。TNF-α通过直接降低成肌细胞和肌管中miR-128 a的表达，促进IRS 1/Akt信号传导，从而促进成肌细胞增殖和肌管肥大。总之，我们证明了miR-128 a调节成肌细胞增殖和肌管肥大，并提供了一种新的机制，通过这种机制，IRS 1依赖性胰岛素信号在骨骼肌中受到调节。
Skeletal muscle possesses a strong ability to regenerate following injury, a fact that has been largely attributed to satellite cells. Satellite cells are skeletal muscle stem cells located beneath the basal lamina of the myofiber, and are the principal cellular source of growth and regeneration in skeletal muscle. MicroRNAs (miRNAs) play key roles in modulating several cellular processes by targeting multiple mRNAs that comprise a single or multiple signaling pathway. Several miRNAs have been shown to regulate satellite cell activity, such as miRNA-489, which functions to maintain satellite cells in a quiescent state. Although muscle-specific miRNAs have been identified, many of the molecular mechanisms that regulate myogenesis that are regulated by miRNAs still remain unknown. In this study, we have shown that miR-128a is highly expressed in brain and skeletal muscle, and increases during myoblast differentiation. MiR-128a was found to regulate the target genes involved in insulin signaling, which include Insr (insulin receptor), Irs1 (insulin receptor substrate 1) and Pik3r1 (phosphatidylinositol 3-kinases regulatory 1) at both the mRNA and protein level. Overexpression of miR-128a in myoblasts inhibited cell proliferation by targeting IRS1. By contrast, inhibition of miR-128a induced myotube maturation and myofiber hypertrophy in vitro and in vivo. Moreover, our results demonstrate that miR-128a expression levels are negatively controlled by tumor necrosis factor alpha (TNF-alpha). TNF-alpha promoted myoblast proliferation and myotube hypertrophy by facilitating IRS1/Akt signaling via a direct decrease of miR-128a expression in both myoblasts and myotubes. In summary, we demonstrate that miR-128a regulates myoblast proliferation and myotube hypertrophy, and provides a novel mechanism through which IRS1-dependent insulin signaling is regulated in skeletal muscle.