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Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy
Yahao Ling1, Jiaxin Ma2, Xiaolong Qi2
1Key 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.
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 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, 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 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.
Results:
ISCA1 expression in myocardium exhibited a semizygous effect. Isca1 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.
Conclusion:
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.
Insights
Researchers developed a new rat model for multiple mitochondrial dysfunction syndromes (MMDS) with cardiac dysplasia. This model aids in studying mitochondrial cardiomyopathy and developing new cardiovascular disease treatments.
Area of Science:
- Mitochondrial Biology
- Cardiovascular Research
- Genetics
Background:
- Multiple mitochondrial dysfunction syndromes (MMDS) cause widespread metabolic impairment.
- Cardiac dysplasia is a known complication of MMDS, but its mechanisms and clinical features are poorly understood.
- A lack of suitable animal models hinders MMDS and cardiac dysplasia research.
Purpose of the Study:
- To establish an animal model for studying MMDS complicated with cardiac dysplasia.
- To investigate the role of the ISCA1 gene in cardiac development and mitochondrial function.
Main Methods:
- Generated myocardium-specific *Isca1* knockout heterozygote (HET) rats by crossing *Isca1* cKO and *α-MHC-Cre* rats.
- Assessed cardiac function using ECG, blood pressure, echocardiography, and histopathology.
- Analyzed mitochondrial function through respiratory chain complex activity and ATP production assays.
Main Results:
- *Isca1* HET rats displayed dilated cardiomyopathy with ventricular thinning, chamber enlargement, cardiac dysfunction, and fibrosis.
- Downregulated ISCA1 expression correlated with cardiac pathology and MMDS characteristics.
- *Isca1* HET rats showed impaired mitochondrial morphology, reduced respiratory chain complex activity (I, II, IV), and decreased ATP production.
Conclusions:
- A novel rat model for MMDS with cardiomyopathy has been successfully created.
- This model is valuable for investigating myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy.
- The model can advance research into cardiovascular disease mechanisms and therapeutic drug development.
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