Key Laboratory of Human Disease Comparative Medicine National Health Commission of China (NHC) Institute of Laboratory Animal Science Peking Union Medical College Chinese Academy of Medical Sciences Beijing China.
Beijing Engineering Research Center for Experimental Animal Models of Human Diseases Institute of Laboratory Animal Science Peking Union Medical College Chinese Academy of Medical Sciences Beijing China.
Animal Model Exp Med. 2021 Dec 6;4(4):381-390. doi: 10.1002/ame2.12193. eCollection 2021 Dec.
Multiple mitochondrial dysfunction syndromes (MMDS) presents as complex mitochondrial damage, thus impairing a variety of metabolic pathways. Heart dysplasia has been reported in MMDS patients; however, the specific clinical symptoms and pathogenesis remain unclear. More urgently, there is a lack of an animal model to aid research. Therefore, we selected a reported MMDS causal gene, , and established an animal model of MMDS complicated with cardiac dysplasia.
The myocardium-specific knockout heterozygote ( HET) rat was obtained by crossing the conditional knockout ( cKO) rat with the () rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopathological analysis. The responsiveness to pathological stimuli were observed through adriamycin treatment. Mitochondria and metabolism disorder were determined by activity analysis of mitochondrial respiratory chain complex and ATP production in myocardium.
ISCA1 expression in myocardium exhibited a semizygous effect. HET rats exhibited dilated cardiomyopathy characteristics, including thin-walled ventricles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organizational levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respiratory chain complexes Ⅰ, Ⅱ and Ⅳ, and impaired ATP production.
We have established a rat model of MMDS complicated with cardiomyopathy, it can also be used as model of myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy. This model can be applied to the study of the mechanism of energy metabolism in cardiovascular diseases, as well as research and development of drugs.
多种线粒体功能障碍综合征（MMDS）表现为复杂的线粒体损伤，从而损害多种代谢途径。已有 MMDS 患者心脏发育不良的报道；然而，具体的临床症状和发病机制尚不清楚。更迫切的是，缺乏一种动物模型来辅助研究。因此，我们选择了一种报道的 MMDS 致病基因，ISCA1，并建立了一种 MMDS 合并心脏发育不良的动物模型。
通过将条件性敲除（cKO）大鼠与 ISCA1 基因敲除（）大鼠杂交，获得心肌特异性 ISCA1 敲除杂合子（HET）大鼠。通过心电图、血压测量、超声心动图和组织病理学分析来确定心脏发育特征。通过阿霉素处理观察对病理刺激的反应。通过心肌线粒体呼吸链复合物活性分析和 ATP 产生来确定线粒体和代谢紊乱。
心肌中 ISCA1 的表达呈现半合子效应。HET 大鼠表现出扩张型心肌病的特征，包括心室壁变薄、心室腔增大、心功能障碍和心肌纤维化。ISCA1 的下调导致心脏病理过程在整体和组织水平上恶化。同时，HET 大鼠表现出典型的 MMDS 特征，包括线粒体形态和线粒体呼吸链复合物Ⅰ、Ⅱ和Ⅳ的酶活性受损，以及 ATP 产生受损。
我们已经建立了一种 MMDS 合并心肌病的大鼠模型，它也可以作为心肌能量代谢障碍和线粒体心肌病的模型。该模型可应用于心血管疾病能量代谢机制的研究以及药物的研发。
