Mst1敲除减轻高脂饮食诱发的心肌线粒体动力学紊乱

董媛; 张　䶮; 封欣妤; 孙东; 满万荣; 宋兴隆; 孙冬冬; 赵志敬

doi:10.12125/j.chj.202007003

Mst1敲除减轻高脂饮食诱发的心肌线粒体动力学紊乱

Mst1 knockout alleviates high-fat diet induced cardiomyocyte mitochondrial dynamics disorder

摘要

摘要:
目的探讨哺乳动物STE20样激酶1（Mst1）基因敲除是否可以减轻高脂饮食导致的心肌线粒体动力学紊乱并探究其机制。
方法 C57BL/6小鼠（WT）和Mst1基因敲除小鼠（Mst1^-/-）(C57BL/6背景)随机分为正常饮食（Normal diet，ND）组和高脂饮食（High-fat diet，HFD）组，连续喂养16w后，检测各组小鼠体质量、心脏重量/胫骨长度和空腹血脂水平，超声心动图评估心脏功能，HE染色及透射电镜观察心肌肥厚和线粒体形态，心肌柠檬酸合酶(CS)活性和ATP含量评价线粒体功能，Western blot检测线粒体动力学相关蛋白的表达水平。
结果与ND+WT组相比，HFD+WT组小鼠出现肥胖、高血脂、心肌肥厚和心脏舒张功能障碍，同时线粒体分裂增多、形态明显受损，心肌CS活性、ATP含量均降低，线粒体分裂蛋白Drp1、Fis1的表达明显上调（P<0.05），融合蛋白Mfn2的表达明显下调（P<0.05）；与HFD+WT组相比，HFD+Mst1^-/-组小鼠心脏舒张功能、线粒体形态与功能的损伤明显减轻，Drp1表达明显下调（P<0.05），Mfn2表达明显上调（P<0.05）。
结论 Mst1基因敲除可以通过抑制线粒体分裂，促进线粒体融合，以维持线粒体动力学稳定，从而减轻脂毒性相关心肌损害。

Abstract:
AIM To investigate whether mammalian STE20-like kinase 1 (Mst1) knockout can reduce high-fat diet induced cardiomyocyte mitochondrial dynamics disorder and elucidate the underlying mechanism.
METHODS C57BL/6 mice (WT) and Mst1 gene knockout mice (Mst1^-/-)(C57BL/6 background) were randomly divided into a normal diet (ND) group and a high-fat diet (HFD) group. After feeding for 16 weeks, each group was measured for body weight, heart weight/tibial length and fasting blood lipid levels. Echocardiography was used to assess cardiac function, HE staining and transmission electron microscopy were used to observe myocardial hypertrophy and mitochondrial morphology, myocardial citrate synthase (CS) activity and ATP content were tested to evaluate mitochondrial function, and expression level of mitochondrial dynamics-related proteins was detected by western blot.
RESULTS Compared with the ND+WT group, mice in the HFD+WT group developed obesity, hyperlipidemia, myocardial hypertrophy and cardiac diastolic dysfunction. At the same time, mitochondrial fission increased and morphology was significantly impaired. Myocardial CS activity and ATP content decreased, and the expression of mitochondrial fission proteins Drp1 and Fis1 was significantly upregulated (P<0.05), and the expression of fusion protein Mfn2 was significantly downregulated (P<0.05); compared with the HFD+WT group, high-fat damage to the heart diastolic function, mitochondrial morphology and function of the HFD+Mst1^-/- group was significantly reduced, Drp1 expression was significantly downregulated (P<0.05), Mfn2 expression was significantly upregulated (P<0.05).
CONCLUSION Mst1 knockout can inhibit mitochondrial fission and promote mitochondrial fusion to maintain mitochondrial dynamic stability, thereby reducing lipotoxicity-related myocardial damage.

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