Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

Wasala, Nalinda B.; Yue, Yongping; Lostal, William; Wasala, Lakmini P.; Niranjan, Nandita; Hajjar, Roger J.; Babu, Gopal J.; Duan, Dongsheng

doi:10.1016/j.ymthe.2019.12.011

Cited by 40 publications

(45 citation statements)

References 59 publications

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“…This finding is in line with abnormally elevated sarcolipin levels in the muscle of DMD patients and mouse models of the disease ( Voit et al, 2017 ). Most interestingly in this context, in recent studies, both a single systemic delivery of SERCA2a with adeno-associated virus ( Wasala et al, 2020 ) and sarcolipin deletion ( Voit et al, 2017 ) improved Ca 2+ recycling and provided considerable benefits in mouse models of DMD.…”

Section: Discussionmentioning

confidence: 99%

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

Szabó

Ebner

Koenig

et al. 2021

Disease Models &Amp; Mechanisms

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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.

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Section: Discussionmentioning

confidence: 99%

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

Szabó

Ebner

Koenig

et al. 2021

Disease Models &Amp; Mechanisms

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“…SERCA activity can be reduced through several mechanisms, including (i) down-regulation of SERCA expression, (ii) posttranslational modification of SERCA protein, and (iii) differential expression and function of SERCA regulators. In the dystrophic myocardium of mouse models and human patients, SERCA2a levels remain unchanged (Voit et al, 2017;Wasala et al, 2020). In the mdx mouse, SERCA1a expression is increased in the spared intrinsic laryngeal and toe muscles but is reduced in the EDL muscle (Dowling et al, 2003;Ferretti et al, 2009).…”

Section: Role Of Serca and Its Regulatorsmentioning

confidence: 99%

“…Irrespective of SERCA levels, SR Ca 2+ uptake is significantly reduced in dystrophin-deficient cardiac and skeletal muscles, indicating decreased SERCA function (Schneider et al, 2013;Voit et al, 2017;Wasala et al, 2020;Mareedu et al, 2021). Oxidative posttranslational modification has been shown to play an important role in SERCA activity in non-dystrophic heart diseases (Lancel et al, 2010;Horakova et al, 2013).…”

Section: Role Of Serca and Its Regulatorsmentioning

confidence: 99%

“…This can be achieved by overexpressing SERCA or by targeting its inhibitors to enhance SERCA activity. Several animal studies have shown the beneficial effects of SERCA overexpression in ameliorating muscular dystrophy in mice (Morine et al, 2010;Goonasekera et al, 2011;Shin et al, 2011;Mazala et al, 2015;Wasala et al, 2020). Transgenic overexpression of SERCA1 in skeletal muscles of mdx mice has been shown to enhance the EC coupling, improve Ca 2+ removal from the cytosol, and attenuate dystrophic phenotypes such as fibrosis and increased serum creatine kinase levels (Goonasekera et al, 2011).…”

Section: Enhancing Sr Ca 2+ Uptakementioning

confidence: 99%

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Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

et al. 2021

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Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

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“…Other studies have reported the beneficial effects of neonatal AAV2/6-SERCA1a overexpression in the diaphragm [ 129 ] as well as cardiac improvements after AAV9-SERCA2a delivery to 12-month-old mdx mice (1 × 10 12 vg particles/mice) [ 130 ]. Long-lasting effects of such therapy were studied by Wasala et al [ 131 ], and the amelioration of cardiomyopathy and skeletal muscle protection was demonstrated after 18 months after a single systemic delivery of SERCA2a isoform (AAV9-SERCA2a; 6 × 10 12 vg particles/3-month-old mdx mouse). SERCA2 was highly overexpressed in the heart and skeletal muscle causing an increase in SR calcium uptake, better physical performance, no signs of myocardial fibrosis, and the improvement in ECG and restoration of ejection fraction in treated dystrophic animals.…”

Section: Gene-based Therapiesmentioning

confidence: 99%

Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: past, present, and future

Łoboda

Dulak

2020

Pharmacol. Rep

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Background Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration and results in functional decline, loss of ambulation and early death of young men due to cardiac or respiratory failure. Although the major cause of the disease has been known for many years—namely mutation in the DMD gene encoding dystrophin, one of the largest human genes—DMD is still incurable, and its treatment is challenging. Methods A comprehensive and systematic review of literature on the gene, cell, and pharmacological experimental therapies aimed at restoring functional dystrophin or to counteract the associated processes contributing to disease progression like inflammation, fibrosis, calcium signaling or angiogenesis was carried out. Results Although some therapies lead to satisfying effects in skeletal muscle, they are highly ineffective in the heart; therefore, targeting defective cardiac and respiratory systems is vital in DMD patients. Unfortunately, most of the pharmacological compounds treat only the symptoms of the disease. Some drugs addressing the underlying cause, like eteplirsen, golodirsen, and ataluren, have recently been conditionally approved; however, they can correct only specific mutations in the DMD gene and are therefore suitable for small sub-populations of affected individuals. Conclusion In this review, we summarize the possible therapeutic options and describe the current status of various, still imperfect, strategies used for attenuating the disease progression.

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Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

Cited by 40 publications

References 59 publications

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

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

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: past, present, and future

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