miR-146a-5p/XIAP介导高强度间歇运动缓解糖尿病小鼠心肌损伤的机制研究

关键词：高强度间歇运动  2型糖尿病  心肌损伤  微小核糖核酸-146a-5p

Keywords:high-intensity interval exercise  type 2 diabetes  myocardial injury  miR-146a-5p

摘要：

      摘要 目的：观察高强度间歇运动对糖尿病诱发心肌损伤的干预效应，探讨潜在的分子机制。 方法：2月龄db/db小鼠随机分为糖尿病对照组（DC）和糖尿病高强度间歇运动组（HE），同龄db/m作为正常对照组（NC），每组10只。DC组与NC组不运动，HE组进行10周高强度间歇运动。采用超声心动图、高通量测序、染色、qRT-PCR、Western Blot等技术检测各组小鼠的心功能、心肌结构、心肌中miRNAs和蛋白表达等情况。 结果：干预10周后小鼠体重和随机血糖DC组和HE组显著高于NC组（P＜0.01），相较于DC组，HE组小鼠体重第2、4、6、8周显著降低（P＜0.05），血糖在第4、6周显著降低（P＜0.05）；NC组心肌肌丝及肌纤维排列整齐，线粒体多分布均匀，无胶原沉积和细胞凋亡，cTnI表达量少，DC组心肌肌丝排列紊乱有断裂，线粒体空泡化严重，肌纤维肥大，有脂滴、大量胶原沉积和易见的凋亡细胞，cTnI表达量显著高于NC组。HE组心肌纤维肥大、线粒体空泡化、脂滴和胶原沉积、细胞凋亡较DC组有改善，cTnI表达量显著降低；LVEF、LVFS、LVIDd指标DC组显著高于NC组（P＜0.01），HE组显著低于DC组（P＜0.05）；DC组心肌中miR-146a-5p、BAX、Caspase-3、Caspase-9、Cytochrome C的表达显著高于NC组（P＜0.01），而HE组显著低于DC组（P＜0.01 or P＜0.05），心肌中XIAP mRNA、XIAP、BCL-2的表达DC组显著低于NC组（P＜0.001 or P＜0.01），HE组显著高于DC组（P＜0.01 or P＜0.05）。 结论：T2DM诱发心脏发生结构损伤和功能代偿，10周HIIT干预通过miR-146a-5p/XIAP信号轴缓解心肌损伤。

Abstract:

      Abstract Objective： To observe the intervention effect of high-intensity interval exercise on diabetes-induced myocardial injury and to explore the potential molecular mechanisms. Method： Two-month-old db/db mice were randomly divided into a diabetic control group （DC） and a diabetic high-intensity interval exercise group （HE）， with db/m mice of the same age as the normal control group （NC）， with 10 mice in each group. The DC group and the NC group did not exercise， while the HE group underwent 10 weeks of high-intensity interval exercise. Echocardiography， high-throughput sequencing， staining， qRT-PCR， Western blot and other technologies were used to assess cardiac function, myocardial structure, myocardial miRNAs, and protein expression in each group of mice. Result： After 10 weeks of intervention, body weight and random blood glucose were significantly higher in the DC and HE groups than in the NC group （P＜0.01）. Compared with the DC group， the body weight of mice in the HE group was significantly decreased at the 2nd， 4th， 6th and 8th weeks （P＜0.05）， while the blood glucose level was significantly reduced at the 4th and 6th weeks （P＜0.05）. In the NC group， myocardial myofilaments and muscle fibers were neatly arranged， mitochondria were evenly distributed， and there was no collagen deposition or apoptosis positive cells, with low cTnI expression. In the DC group， myocardial myofilaments were disordered and broken， mitochondrial vacuolization was severe， and fibers were hypertrophic. There were also lipid droplets， a large amount of collagen deposition， and visible apoptotic positive cells. The expression level of cTnI was significantly higher than that in the NC group. Compared to the DC group， myocardial fiber hypertrophy， mitochondrial vacuolization， lipid droplets， collagen deposition， apoptosis were improved in the HE group， and the expression level of cTnI was significantly reduced. LVEF， LVFS， and LVIDd indices were significantly higher in the DC group than in the NC group （P＜0.01）， and were significantly lower in the HE group than in the DC group （P＜0.05）. miR-146a-5p， BAX， Caspase-3， Caspase-9， and Cytochrome C expression in the myocardium of the DC group was significantly higher than that in the NC group （P＜0.01）， and was significantly lower in the HE group than in the DC group （P＜0.01 or P＜0.05）. The expression of XIAP mRNA， XIAP， and BCL-2 in the myocardium of the DC group was significantly lower than that in the NC group （P＜0.001 or P＜0.01）， and was significantly higher in the HE group than in the DC group （P＜0.01 or P＜0.05）. Conclusion： T2DM induces structural damage and functional compensation in the heart， and 10 weeks of high-intensity interval exercise alleviates myocardial injury via the miR-146a-5p/XIAP signaling axis.