Cardiovascular phenotype of the Dmdmdx 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 Dmdmdx 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 Dmdmdx rats, and to characterize the Dmdmdx 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 Dmdmdx rats show significantly impaired cardiac function, fibrosis and inflammation, consistent with the development of a dilated cardiomyopathy. Moreover, in Dmdmdx rats, vascular endothelial function is impaired, which may relate to inflammation and oxidative stress, and Ca2+ handling in Dmdmdx cardiomyocytes is abnormal.These findings indicate that Dmdmdx 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.

Transcriptomic analysis of mdx mouse muscles reveals a signature of early human Duchenne muscular dystrophy

“…For example, the D2mdx mouse, which has the DBA/2 instead of the C57BL/10 genetic background [29,55], may be useful for investigating fibrosis since D2-mdx shows fibrosis in the diaphragm and in hindlimb muscles while mdx shows fibrosis in the diaphragm only [14]. Several new animal lines seem to be better models of the cardiac than of the skeletal aspects of DMD: the Cmah-/-;-mdx mouse, which carries a human-like mutation in a gene involved in sialylation [28,56]; the mdx/mTR mouse [27,57] which has shorter telomeres than the mdx mouse, as in the human disease; and a new mdx rat model [58]. Different mouse lines have been compared for studies of bone defects [59] which the mdx mouse does not mimic well [60] although it has been used successfully to study pharmacological effects on bone [61].…”

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

“…All of these clinical signs and pathological features are much more pronounced than in Dmd KO mice. Rats are becoming an increasingly used model for the study of different aspects of Duchenne's and Becker's myopathies, including biomarkers, neurological abnormalities, and immune/inflammatory responses (Robertson et al, 2017;Ouisse et al, 2019;Caudal et al, 2020;Szabó et al, 2021).…”

Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

“…ACE and ACE2 activities in cardiac (infarcted and non-infarcted) tissue samples were measured as described previously [40,41]. Briefly, tissue samples were weighed, and a proportional amount of 100 mM tris(hydroxymethyl)aminomethane hydrochloride (TRIS) buffer (pH 7.0) was added then homogenized.…”