老化的骨骼肌显示代谢功能的扰动。MicroRNAs已被证明在骨骼肌的衰老和代谢功能中起关键作用。microRNA-34a(miR-34a)与大脑和心脏衰老有关,然而,其在肌肉衰老中的作用尚不清楚。我们分析了miR-34a的水平,神经酰胺激酶(CERK)和其他胰岛素信号分子在老年小鼠骨骼肌中。除了体内模型,还在源自胰岛素抵抗(IR)人的成肌细胞和过表达mir-34a的C2C12成肌细胞中分析了这些分子的水平。我们的结果表明,miR-34a在2岁小鼠的肌肉和IR人类的成肌细胞中升高。miR-34a在C2C12成肌细胞中的过表达导致胰岛素信号通路的改变,被它的对抗拯救了。我们的分析显示,miR-34a靶向CERK导致神经酰胺积累,肌肉和C2C12成肌细胞中PP2A和pJNK途径的激活。此外,肌肉生长抑制素(Mstn)水平在2岁小鼠肌肉中增加,并且Mstn处理上调C2C12成肌细胞中的miR-34a。此外,miR-34a表达和神经酰胺水平在Mstn-/-小鼠肌肉的衰老过程中没有增加。总之,我们,因此,提出Mstn水平在衰老肌肉中增加并上调miR-34a,抑制CERK导致神经酰胺水平增加。这种神经酰胺的积累激活PP2A和pJNK,导致AKT的低磷酸化和IRS1(Ser307)的过度磷酸化,分别,损伤胰岛素信号通路并最终抑制GLUT4的肌膜定位。这些变化将导致葡萄糖摄取减少和胰岛素抵抗。本研究首次通过基于miR-34a的机制解释衰老肌肉中神经酰胺积累和胰岛素信号通路受损的现象。总之,我们的结果表明,Mstn和miR-34a拮抗作用有助于改善衰老骨骼肌中神经酰胺的积累和胰岛素敏感性的丧失.
Aging skeletal muscle shows perturbations in metabolic functions. MicroRNAs have been shown to play a critical role in aging and metabolic functions of skeletal muscle. MicroRNA-34a (miR-34a) is implicated in the brain and cardiac aging, however, its role in aging muscle is unclear. We analyzed levels of miR-34a, ceramide kinase (
CERK) and other insulin signaling molecules in skeletal muscle from old mice. In addition to in vivo model, levels of these molecules were also analyzed in myoblast derived from insulin resistant (IR) humans and C2C12 myoblasts overexpressing mir-34a. Our results show that miR-34a is elevated in the muscles of 2-year-old mice and in the myoblasts of IR humans. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which were rescued by its antagonism. Our analyses revealed that miR-34a targets
CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Also, myostatin (Mstn) levels were increased in 2-year-old mouse muscle and Mstn treatment upregulated miR-34a in C2C12 myoblasts. In addition, miR-34a expression and ceramide levels did not increase during aging in Mstn-/- mice muscle. In summary, we, therefore, propose that Mstn levels increase in aging muscle and upregulate miR-34a, which inhibits
CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of IRS1 (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes would result in reduced glucose uptake and insulin resistance. This study is the first to explain the phenomenon of ceramide accrual and impairment of insulin signaling pathway in aging muscle through a miR-34a based mechanism. In conclusion, our results suggest that Mstn and miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle.