TMAO Inhibitors' Effects on Diabetic Sarcopenia in Rats
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摘要:
目的 探究氧化三甲胺（TMAO）抑制剂对糖尿病性肌少症大鼠线粒体损伤、骨骼肌功能及微血管衰老的影响。 方法 无特定病原体级实验动物（SPF）级别雄性大鼠构建糖尿病性肌少症动物模型，3，3-二甲基-1-丁醇（DMB）干预。检测各组大鼠空腹血糖、胰岛素及胰岛素抵抗指数；抓绳实验、腓肠肌重量、体重检测；腓肠肌病理形态；线粒体膜电位检测及超微结构；微血管衰老相关蛋白基质金属蛋白酶（MMP）-2、单核细胞趋化蛋白（MCP）-1、转化生长因子（TGF）-β1表达。 结果 与健康组大鼠相比，模型组胰岛素、抓绳时间、体重、腓肠肌重量、腓/体比值、线粒体膜电位均降低，空腹血糖、胰岛素抵抗指数、MMP-2、MCP-1、TGF-β1均升高（P < 0.05）；与模型组相比，0.1%DMB组胰岛素、抓绳时间、体重、腓肠肌重量、腓/体比值、线粒体膜电位均升高，空腹血糖、胰岛素抵抗指数、MMP-2、MCP-1、TGF-β1均降低（P < 0.05）。 结论 TMAO抑制剂可降低空腹血糖及胰岛素抵抗，改善线粒体损伤而提高骨骼肌功能，可能是通过抑制MMP-2、MCP-1、TGF-β1表达而减少微血管衰老。 Abstract:Objective To investigate the effects of trimethylamine N-oxide （TMAO） inhibitor on mitochondrial damage, skeletal muscle function, and microvascular senescence in rats with diabetic sarcopenia. Methods An animal model of diabetic sarcopenia was established in specific pathogen-free experimental animal （SPF） grade male rats, and intervention was carried out with 3, 3-dimethyl-1-butanol （DMB）. The fasting blood glucose, insulin and insulin resistance index of rats in each group were detected. Rope grasping test, gastrocnemius muscle weight, body weight detection; Pathological morphology of the gastrocnemius muscle Detection of mitochondrial membrane potential and ultrastructure Expression of microvascular aging-related proteins matrix metalloproteinase （MMP） -2, monocyte chemoattractant protein （MCP） -1, and transforming growth factor （TGF） -β1. Results Compared with the healthy control group, the model group showed significant decreases in insulin level, wire-hanging time, body weight, gastrocnemius muscle weight, gastrocnemius-to-body weight ratio, and mitochondrial membrane potential, along with significant increases in FBG, HOMA-IR, and the expression levels of MMP-2, MCP-1, and TGF-β1 （all P < 0.05）. Compared with the model group, the 0.1% DMB group exhibited significant increases in insulin level, wire-hanging time, body weight, gastrocnemius muscle weight, gastrocnemius-to-body weight ratio, and mitochondrial membrane potential, as well as significant decreases in FBG, HOMA-IR, and the expression levels of MMP-2, MCP-1, and TGF-β1 （all P < 0.05）. Conclusion TMAO inhibitor can reduce FBG and insulin resistance, alleviate mitochondrial damage, and thereby improve skeletal muscle function in rats with diabetic sarcopenia. This effect is presumably achieved by inhibiting the expression of MMP-2, MCP-1, and TGF-β1 to reduce microvascular senescence. -
Key words:
- Diabetic Sarcopenia /
- Trimethylamine N-Oxide （TMAO） /
- Mitochondria /
- Skeletal Muscle /
- Vascular Aging
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图 1 各组大鼠腓肠肌病理形态比较（苏木精-伊红染色，200×）
注：黑色箭头为腓肠肌排序萎缩
Figure 1. Comparison of the pathological morphology of the gastrocnemius muscle in each group of rats （hematoxylin-eosin staining，200×）
图 2 各组大鼠空腹血糖、胰岛素及胰岛素抵抗指数比较[（$\bar x \pm s $） ，n = 12]
A：空腹血糖，B：胰岛素水平；C：胰岛素抵抗指数比；与健康组相比，①P < 0.05；与模型组相比，②P < 0.05；0.05%DMB组相比，③P < 0.05；
Figure 2. Comparison of fasting blood glucose，insulin and insulin resistance index of rats in each group[（$\bar x \pm s $） ，n = 12]
图 3 各组大鼠抓绳时间、体重、腓肠肌总量及腓/体比较[（$\bar x \pm s $） ，n = 12]
A：抓绳时间；B：体重；C：腓肠肌总量；D：腓/体；与健康组相比，①P < 0.05；与模型组相比，②P < 0.05；0.05%DMB组相比，③P < 0.05；与0.1%DMB组相比，④P < 0.05；
Figure 3. shows the comparison of rope grasping time，body weight，total gastrocnemius muscle and fibular/body weight of rats in each group[（$\bar x \pm s $） ，n = 12]
图 4 各组大鼠线粒体超微结构、线粒体膜电位比较[（锇酸染色，
5000 ×），（$\bar x \pm s $） ，n = 12]注：红色箭头为线粒体肿胀。A：线粒体超微结构；B：线粒体膜电位；与健康组相比，①P < 0.05；与模型组相比，②P < 0.05；0.05%DMB组相比，③P < 0.05；与0.1%DMB组相比，④P < 0.05。
Figure 4. Comparison of mitochondrial ultrastructure and mitochondrial membrane potential in each group of rats[（osmium acid staining，
5000 ×），（$\bar x \pm s $），n = 12]
图 5 各组大鼠MMP-2 、MCP-1及TGF-β1蛋白图及表达比较[（$\bar x \pm s $），n = 12]
注：A：MMP-2 、MCP-1及TGF-β1蛋白图；B：MMP-2 、MCP-1及TGF-β1蛋白表达；与健康组相比，①P < 0.05；与模型组相比，②P < 0.05；0.05%DMB组相比，③P < 0.05；与0.1%DMB组相比，④P < 0.05。
Figure 5. Protein diagrams and expression comparisons of MMP-2，MCP-1 and TGF-β1 in each group of rats [（$\bar x \pm s $），n = 12]
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