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Cardiovascular phenotype of the Dmd^mdx rat - a suitable animal model for Duchenne muscular dystrophy.

ABSTRACT: Besides skeletal muscle abnormalities, Duchenne muscular dystrophy (DMD) patients present with dilated cardiomyopathy development, which considerably contributes to morbidity and mortality. Because the mechanisms responsible for the cardiac complications in the context of DMD are largely unknown, evidence-based therapy approaches are still lacking. This has increased the need for basic research efforts into animal models for DMD. Here, we characterized in detail the cardiovascular abnormalities of Dmd^mdx rats, with the aim of determining the suitability of this recently established dystrophin-deficient small animal as a model for DMD.Various methods were applied to compare cardiovascular properties between wild-type and Dmd^mdx rats, and to characterize the Dmd^mdx cardiomyopathy. These methods comprised echocardiography, invasive assessment of left ventricular hemodynamics, examination of adverse remodeling and endothelial cell inflammation, and evaluation of vascular function, employing wire myography. Finally, intracellular Ca²⁺ transient measurements, and recordings of currents through L-type Ca²⁺ channels were performed in isolated single ventricular cardiomyocytes. We found that, similar to respective observations in DMD patients, the hearts of Dmd^mdx rats show significantly impaired cardiac function, fibrosis and inflammation, consistent with the development of a dilated cardiomyopathy. Moreover, in Dmd^mdx rats, vascular endothelial function is impaired, which may relate to inflammation and oxidative stress, and Ca²⁺ handling in Dmd^mdx cardiomyocytes is abnormal.These findings indicate that Dmd^mdx rats represent a promising small-animal model to elucidate mechanisms of cardiomyopathy development in the dystrophic heart, and to test mechanism-based therapies aiming to combat cardiovascular complications in DMD.

SUBMITTER: Szabo PL

PROVIDER: S-EPMC7927653 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Cardiovascular phenotype of the <i>Dmd<sup>mdx</sup></i> rat - a suitable animal model for Duchenne muscular dystrophy.

Szabó Petra Lujza PL Ebner Janine J Koenig Xaver X Hamza Ouafa O Watzinger Simon S Trojanek Sandra S Abraham Dietmar D Todt Hannes H Kubista Helmut H Schicker Klaus K Remy Séverine S Anegon Ignacio I Kiss Attila A Podesser Bruno K BK Hilber Karlheinz K

Disease models & mechanisms 20210222 2

Besides skeletal muscle abnormalities, Duchenne muscular dystrophy (DMD) patients present with dilated cardiomyopathy development, which considerably contributes to morbidity and mortality. Because the mechanisms responsible for the cardiac complications in the context of DMD are largely unknown, evidence-based therapy approaches are still lacking. This has increased the need for basic research efforts into animal models for DMD. Here, we characterized in detail the cardiovascular abnormalities ...[more]

PMID: 33619211

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Project description:The mdx mouse is the most widely-used animal model of the human disease Duchenne muscular dystrophy, and quantitative PCR analysis of gene expression in the muscles of this animal plays a key role in the study of pathogenesis and disease progression and in evaluation of potential therapeutic interventions. Normalization to appropriate stably-expressed reference genes is essential for accurate quantitative measurement, but determination of such genes is challenging: healthy and dystrophic muscles present very different transcriptional environments, further altering with disease progression and muscle use, raising the possibility that no single gene or combination of genes may be stable under all experimental comparative scenarios. Despite the pedigree of this animal model, this problem remains unaddressed. The aim of this work was therefore to comprehensively assess reference gene suitability in the muscles of healthy and dystrophic mice, identifying reference genes appropriate for specific experimental comparisons, and determining whether an essentially universally-applicable set of genes exists. Using a large sample collection comprising multiple muscles (including the tibialis anterior, diaphragm and heart muscles) taken from healthy and mdx mice at three disease-relevant ages, and a panel of sixteen candidate reference genes (FBXO38, FBXW2, MON2, ZFP91, HTATSF1, GAPDH, ACTB, 18S, CDC40, SDHA, RPL13a, CSNK2A2, AP3D1, PAK1IP1, B2M and HPRT1), we used the geNorm, BestKeeper and Normfinder algorithms to identify genes that were stable under multiple possible comparative scenarios. We reveal that no single gene is stable under all conditions, but a normalization factor derived from multiple genes (RPL13a, CSNK2A2, AP3D1 and the widely-used ACTB) appears suitable for normalizing gene expression in both healthy and dystrophic mouse muscle regardless of muscle type or animal age. We further show that other popular reference genes, including GAPDH, are markedly disease- or muscle-type correlated. This study demonstrates the importance of empirical reference gene identification, and should serve as a valuable resource for investigators wishing to study gene expression in mdx mice.

Dataset Information

Cardiovascular phenotype of the Dmd^mdx rat - a suitable animal model for Duchenne muscular dystrophy.

Publications

Cardiovascular phenotype of the <i>Dmd<sup>mdx</sup></i> rat - a suitable animal model for Duchenne muscular dystrophy.

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Dataset Information

Cardiovascular phenotype of the Dmdmdx rat - a suitable animal model for Duchenne muscular dystrophy.

Publications

Cardiovascular phenotype of the <i>Dmd<sup>mdx</sup></i> rat - a suitable animal model for Duchenne muscular dystrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Cardiovascular phenotype of the Dmd^mdx rat - a suitable animal model for Duchenne muscular dystrophy.