miR-23a在小鼠骨骼肌胰岛素抵抗中的作用及机制

Decreased skeletal muscle mass is one of the most important reasons of insulin resistance (IR). Our previous research showed that the expression of miR-23a was decreased in skeletal muscle, and its expression level was positively correlated with skeletal muscle mass in insulin resistance animal model caused by catch-up growth. Moreover, with the help of the bioinformatics software, we noticed that FOXO3 might be suppressed by miR-23a. It has been demonstrated that FOXO3 is a key regulator for activity of ubiquitin-proteasome pathway, which is associated with skeletal muscle mass. Thus, our hypothesis is that miR-23a may decrease FOXO3 expression level, suppressing ubiquitin-proteasome pathway and leading to prevention of skeletal muscle mass decrease, which finally result in improvement of insulin resistance. By applying mice IR model, we will observe changes of miR-23a expression，the protein level of FOXO3 and activation of UPP pathway. At the same time, we will block or enhance the utility of miRNA-23a to clarify its impact on the IR of skeletal muscle. Then, we will try to elucidate the specific mechanism of miR-23a regulating skeletal muscle mass and IR. This study may provide new clues for clinical treatment of IR.

骨骼肌肌量减少是胰岛素抵抗(IR)发生的重要因素。前期研究显示：在追赶生长引起IR的动物模型中，miR-23a表达减少，其含量与骨骼肌含量正相关。信息学查询提示miR-23a对FOXO3可能有抑制作用。FOXO3是激活泛素-蛋白酶体途径(UPP)的关键分子，后者的激活引起骨骼肌蛋白降解致肌量减少。故我们推测：miR-23a可能通过抑制 FOXO3表达，下调UPP活性，使骨骼肌蛋白降解减少，进而延缓IR的发生。本课题拟以小鼠作为IR模型①动态观察IR进程中不同时间点miR-23a表达的改变，FOXO3及UPP通路的活化情况。并阻断或增强miRNA-23a的效用，明确其对骨骼肌含量以及IR的影响；②观察miRNA-23a对IR骨骼肌含量相关信号通路（FOXO3及UPP）活性的影响，阐明miRNA-23a介导IR的具体机制。本研究有望揭示miR-23a调控IR的新机制，并为临床治疗提供新线索。

骨骼肌肌量减少是胰岛素抵抗(IR)发生的重要因素。前期研究显示：在追赶生长引起IR的动物模型中，miR-23a表达减少，其含量与骨骼肌含量正相关。信息学查询提示miR-23a对FOXO3可能有抑制作用。FOXO3是激活泛素-蛋白酶体途径(UPP)的关键分子，后者的激活引起骨骼肌蛋白降解致肌量减少。故我们推测：miR-23a可能通过抑制 FOXO3表达，下调UPP活性，使骨骼肌蛋白降解减少，进而延缓IR的发生。本研究通过构建胰岛素抵抗小鼠模型，观察到miRNA-23a的表达随着胰岛素抵抗的严重加剧而减少、FOXO3、UPP通路活性却与胰岛素敏感性成反比。从而明确了追赶生长对骨骼肌干细胞数量、骨骼肌细胞含量、以及胰岛素敏感性的影响。并通过离体和在体两方面的过表达miR-23a，观察到胰岛素抵抗的改善，从而阐明了miRNA-23a 在追赶生长动物发生胰岛素抵抗过程中的作用及具体机制，并为靶向纠正追赶生长胰岛素抵抗提供实验室依据。