DOI: 10.1002/ame2.12193
Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy
Yahao Ling1
Jiaxin Ma2
Xiaolong Qi2
Xu Zhang2
Qi Kong2
Feifei Guan2
Wei Dong1
Wei Chen1
Shan Gao1
Xiang Gao1
Shuo Pan2
Yuanwu Ma1
Dan Lu2
Lianfeng Zhang1
1.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,China2.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
摘要：Background : 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 symp-toms 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, Isca1 , and established an animal model of MMDS complicated with cardiac dysplasia.Methods : The myocardium- specific Isca1 knockout heterozygote ( Isca1 HET) rat was obtained by crossing the Isca1 conditional knockout ( Isca1 cKO) rat with the α myosin heavy chain Cre ( α- MHC- Cre ) rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopatho-logical 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. Results : ISCA1 expression in myocardium exhibited a semizygous effect. I sca1 HET rats exhibited dilated cardiomyopathy characteristics, including thin- walled ventri-cles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organiza-tional levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respira-tory chain complexes Ⅰ, Ⅱ and Ⅳ, and impaired ATP production. Conclusion : We have established a rat model of MMDS complicated with cardiomyo-pathy, 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.
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论文发表日期：2021-12-25
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：10( 381-390 )
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