Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy

Ling, Yahao; Ma, Jiaxin; Qi, Xiaolong; Zhang, Xu; Kong, Qi; Guan, Feifei; Dong, Wei; Chen, Wei; Gao, Shan; Gao, Xiang; Pan, Shuo; Ma, Yuanwu; Lu, Dongfang; Zhang, Lianfeng

doi:10.1002/ame2.12193

Cited by 5 publications

(7 citation statements)

References 41 publications

(111 reference statements)

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“…The measurements were recorded as the average of at least three consecutive cardiac cycles. The LVDS, LVDD, LVPWS, LV posterior wall thickness at end diastole (LVPWD), SV, LVFS and LV mass were analyzed with Vevo LAB 5.5.0 ( Ling et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway

Jiang

Guan

et al. 2022

Disease Models &Amp; Mechanisms

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When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3β/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF.

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Section: Methodsmentioning

confidence: 99%

Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway

Jiang

Guan

et al. 2022

Disease Models &Amp; Mechanisms

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“…Ling et al developed a promising heterozygote knockout rat for the myocardium-specific Isca1 , a causal gene for multiple mitochondrial dysfunction syndromes with cardiac dysplasia [ 129 ]. From 3 months of age, rats manifest an echocardiographic and histopathological phenotype of DCM, characterized by LV wall thinning and dilatation, contractile impairment, myocardial lysis and fibrosis.…”

Section: Genetic Modelsmentioning

confidence: 99%

“…From 3 months of age, rats manifest an echocardiographic and histopathological phenotype of DCM, characterized by LV wall thinning and dilatation, contractile impairment, myocardial lysis and fibrosis. The subcellular mechanisms of mitochondrial dysfunction syndromes were clearly represented in this model, with swollen mitochondria containing damaged membrane structure and partial absence of crests, together with reduced expression levels of key enzymes for ATP synthesis and iron homeostasis [ 129 , 130 ].…”

Section: Genetic Modelsmentioning

confidence: 99%

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

Ponzoni

Coles

Maynes

2023

IJMS

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Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided.

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“…Sayles et al reported that mutant CHCHD10 and/or CHCHD2 proteotoxicity activate the mitochondrial integrated stress response (ISR mt ), which causes profound metabolic imbalances, culminating in oxidative stress and iron dysregulation, and ultimately resulting in mitochondrial dysfunction and contributing to disease pathogenesis [ 28 , 29 ]. Recently, a myocardium-specific Isca1 knockout rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy was applied to study the mechanism of energy metabolism in cardiovascular diseases, as well as for the development of drugs [ 30 ]. Nevertheless, the specific mechanisms that underlie cardiac developmental disorders are not yet well understood, and there is an urgent need for suitable in vivo animal models to aid research.…”

Section: Disease Modeling For MCMmentioning

confidence: 99%

Mitochondrial Cardiomyopathy: Molecular Epidemiology, Diagnosis, Models, and Therapeutic Management

Yang

Chen

Duan

et al. 2022

Cells

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Mitochondrial cardiomyopathy (MCM) is characterized by abnormal heart-muscle structure and function, caused by mutations in the nuclear genome or mitochondrial DNA. The heterogeneity of gene mutations and various clinical presentations in patients with cardiomyopathy make its diagnosis, molecular mechanism, and therapeutics great challenges. This review describes the molecular epidemiology of MCM and its clinical features, reviews the promising diagnostic tests applied for mitochondrial diseases and cardiomyopathies, and details the animal and cellular models used for modeling cardiomyopathy and to investigate disease pathogenesis in a controlled in vitro environment. It also discusses the emerging therapeutics tested in pre-clinical and clinical studies of cardiac regeneration.

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Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 41 publications

Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway

Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

Mitochondrial Cardiomyopathy: Molecular Epidemiology, Diagnosis, Models, and Therapeutic Management

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