ob/ob小鼠心肌线粒体相关网状膜的结构和功能表征

Hala Guedouari , Maya Dia , Juliette Geoffray , Camille Brun , Florentin Moulin , Lucas Givre , Lucid Belmudes , Christelle Leon , Stephanie Chanon , Jingwei Ji-Cao , Christophe Chouabe , Sylvie Ducreux , Claire Crola Da Silva , Ludovic Gomez , Yohann Couté , Helene Thibault , Jennifer Rieusset , Melanie Paillard
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引用次数: 0

摘要

2型糖尿病(T2D)和肥胖强烈导致糖尿病性心肌病(DCM)。线粒体相关网状膜(MAMs)是心肌细胞的信号中枢,在t2d相关代谢紊乱中开始得到证实。我们最近在高脂肪高糖饮食(HFHSD)诱导的DCM小鼠模型中发现心脏MAM Ca2+解偶联。为了更好地确定MAMs在DCM进展中的作用,我们在这里旨在表征另一种致肥性T2D小鼠模型(瘦素缺乏的ob/ob小鼠)心脏MAMs的蛋白质组学组成和功能。12周龄雄性C57Bl6-N ob/ob小鼠表现出应变率功能障碍和同心重构,而分数缩短和舒张功能未见变化。与WT相比,ob/ob心脏中脂质沉积增加,但未见纤维化。电镜分析显示,两组心脏MAM的长度和宽度相似。在ob/ob心脏中测量到MAM蛋白含量增加的趋势。MAM蛋白质组分析显示,ob/ob心脏中主要增加的过程是:细胞对应激的反应、脂质代谢、离子转运和膜组织。功能上,mam驱动的Ca2+通量不变,但缺氧应激诱导ob/ob心肌细胞死亡增加。各组间线粒体呼吸、心肌细胞缩短、ATP和ROS含量相似。综上所述,在这个年龄,虽然存在强烈的高血糖和胰岛素抵抗,但ob/ob小鼠模型显示出适度的DCM,没有MAMs的强烈变化:保留了结构和功能的MAM Ca2+偶联,但增加了对应激的反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model
Type 2 diabetes (T2D) and obesity strongly lead to diabetic cardiomyopathy (DCM). The involvement of mitochondria-associated reticular membranes (MAMs), a signaling hub in the cardiomyocyte, starts to be demonstrated in T2D-related metabolic disorders. We recently discovered a cardiac MAM Ca2+ uncoupling in a high-fat high-sucrose diet (HFHSD)-induced mouse model of DCM. To better determine the role of MAMs in the progression of DCM, we here aimed to characterize the proteomic composition and function of the cardiac MAMs of another obesogenic T2D mouse model, the leptin-deficient ob/ob mouse.
12-week old male C57Bl6-N ob/ob mice displayed strain rate dysfunction and concentric remodeling, while no change was observed in fractional shortening or diastolic function. Increased lipid deposition but no fibrosis was measured in the ob/ob heart compared to WT. Electron microscopy analysis revealed that cardiac MAM length and width were similar between both groups. A trend towards an increased MAM protein content was measured in the ob/ob heart. MAM proteome analyses showed mainly increased processes in ob/ob hearts: cellular response to stress, lipid metabolism, ion transport and membrane organization. Functionally, MAM-driven Ca2+ fluxes were unchanged but hypoxic stress induced a cell death increase in the ob/ob cardiomyocyte. Mitochondrial respiration, cardiomyocyte shortening, ATP and ROS content were similar between groups.
To conclude, at that age, while being strongly hyperglycemic and insulin-resistant, the ob/ob mouse model rather displays a modest DCM without strong changes in MAMs: preserved structural and functional MAM Ca2+ coupling but increased response to stress.
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来源期刊
Journal of molecular and cellular cardiology plus
Journal of molecular and cellular cardiology plus Cardiology and Cardiovascular Medicine
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