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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, <jats:italic>Isca1<\/jats:italic>, and established an animal model of MMDS complicated with cardiac dysplasia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The myocardium\u2010specific <jats:italic>Isca1<\/jats:italic> knockout heterozygote (<jats:italic>Isca1<\/jats:italic> HET) rat was obtained by crossing the <jats:italic>Isca1<\/jats:italic> conditional knockout (<jats:italic>Isca1<\/jats:italic> cKO) rat with the <jats:italic>\u03b1 myosin heavy chain Cre<\/jats:italic> (<jats:italic>\u03b1\u2010MHC\u2010Cre<\/jats:italic>) 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ISCA1 expression in myocardium exhibited a semizygous effect. <jats:italic>Isca1<\/jats:italic> HET rats exhibited dilated cardiomyopathy characteristics, including thin\u2010walled 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 \u2160, \u2161 and \u2163, and impaired ATP production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ame2.12193","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T04:53:00Z","timestamp":1638852780000},"page":"381-390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy"],"prefix":"10.1002","volume":"4","author":[{"given":"Yahao","family":"Ling","sequence":"first","affiliation":[{"name":"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 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