Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy.

Xinyu Feng,Dongdong Sun,Jie Lin,Wanrong Man,Zhijing Zhao,Xingjun Yang,Yan Zhang,Yuan Dong,Shanjie Wang,Haichang Wang

doi:10.3389/fcell.2020.628842

Xinyu Feng, Dongdong Sun + Show 8 more

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https://doi.org/10.3389/fcell.2020.628842

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Abstract

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.

Highlights

The International Diabetes Federation (IDF) highlights that the global prevalence of diabetes has been increasing over recent decades
In diabetic mice, decreased Left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) and increased left ventricular end-systolic diameter (LVESD) and Left ventricular end-diastolic diameter (LVEDD) were observed as compared with the WT mice
Hemodynamic measurements revealed that Mammalian sterile 20-like kinase 1 (Mst1) knockout decreased ± LV dp/dt max and alleviated cardiac dysfunction in diabetic mice (Figures 1F,G)

Summary

Introduction

The International Diabetes Federation (IDF) highlights that the global prevalence of diabetes has been increasing over recent decades. Diabetes itself is an independent risk factor for cardiovascular disease, and the increased prevalence of diabetes has led to more cases of cardiovascular complications (Adeva-Andany et al, 2019). With the chronic and progressive damage of diabetes, diabetic cardiomyopathy (DCM) which is characterized by early cardiac. It is important to elucidate the mechanism of diabetic cardiomyopathy to reduce the cardiac mortality of diabetic patients. Mitochondrial dynamics are mainly controlled by the two opposing processes of fission and fusion (Mattie et al, 2019). Dysregulation of mitochondrial dynamics has been hypothesized to contribute to the pathogenic progression of metabolic diseases, including the diabetic complication of DCM (Galloway and Yoon, 2015). The molecular mechanisms responsible for mitochondrial dynamics in diabetic stress are not well-understood

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