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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