Dataset Information

Dwarf Open Reading Frame (DWORF) Gene Therapy Ameliorated Duchenne Muscular Dystrophy Cardiomyopathy in Aged mdx Mice.

ABSTRACT: Background Cardiomyopathy is a leading health threat in Duchenne muscular dystrophy (DMD). Cytosolic calcium upregulation is implicated in DMD cardiomyopathy. Calcium is primarily removed from the cytosol by the sarcoendoplasmic reticulum calcium ATPase (SERCA). SERCA activity is reduced in DMD. Improving SERCA function may treat DMD cardiomyopathy. Dwarf open reading frame (DWORF) is a recently discovered positive regulator for SERCA, hence, a potential therapeutic target. Methods and Results To study DWORF's involvement in DMD cardiomyopathy, we quantified DWORF expression in the heart of wild-type mice and the mdx model of DMD. To test DWORF gene therapy, we engineered and characterized an adeno-associated virus serotype 9-DWORF vector. To determine if this vector can mitigate DMD cardiomyopathy, we delivered it to 6-week-old mdx mice (6×10¹² vector genome particles/mouse) via the tail vein. Exercise capacity, heart histology, and cardiac function were examined at 18 months of age. We found DWORF expression was significantly reduced at the transcript and protein levels in mdx mice. Adeno-associated virus serotype 9-DWORF vector significantly enhanced SERCA activity. Systemic adeno-associated virus serotype 9-DWORF therapy reduced myocardial fibrosis and improved treadmill running, electrocardiography, and heart hemodynamics. Conclusions Our data suggest that DWORF deficiency contributes to SERCA dysfunction in mdx mice and that DWORF gene therapy holds promise to treat DMD cardiomyopathy.

SUBMITTER: Morales ED

PROVIDER: S-EPMC9973626 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Dwarf Open Reading Frame (DWORF) Gene Therapy Ameliorated Duchenne Muscular Dystrophy Cardiomyopathy in Aged mdx Mice.

Morales Emily D ED Yue Yongping Y Watkins Thais B TB Han Jin J Pan Xiufang X Gibson Aaron M AM Hu Bryan B Brito-Estrada Omar O Yao Gang G Makarewich Catherine A CA Babu Gopal J GJ Duan Dongsheng D

Journal of the American Heart Association 20230125 3

Background Cardiomyopathy is a leading health threat in Duchenne muscular dystrophy (DMD). Cytosolic calcium upregulation is implicated in DMD cardiomyopathy. Calcium is primarily removed from the cytosol by the sarcoendoplasmic reticulum calcium ATPase (SERCA). SERCA activity is reduced in DMD. Improving SERCA function may treat DMD cardiomyopathy. Dwarf open reading frame (DWORF) is a recently discovered positive regulator for SERCA, hence, a potential therapeutic target. Methods and Results T ...[more]

PMID: 36695318

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Project description:Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5000 male births worldwide. DMD is caused by mutations in the dystrophin gene. Dystrophin is essential for maintaining muscle cell membrane integrity and stability by linking the cytoskeleton to the extracellular matrix, which protects myofibers from contraction-induced damage. Loss of dystrophin leads to mechanically induced skeletal and cardiac muscle damage. Although the disease is not evident in DMD patients at birth, muscular dystrophy rapidly progresses and results in respiratory and cardiac muscle failure as early as the teenage years. Premature death in DMD patients is due to cardiac arrhythmias and left ventricular dysfunction. Currently, there is no effective treatment for DMD-related cardiac failure. Recently, we have shown that a Food and Drug Administration-approved small molecule, sunitinib, a multi-targeted tyrosine kinase inhibitor can mitigate skeletal muscle disease through an increase in myogenic capacity, cell membrane integrity, and improvement of skeletal muscle function via regulation of STAT3-related signaling pathway. Chronic activation of STAT3 has been shown to promote cardiac hypertrophy and failure. In this study, we examined the effects of long-term sunitinib treatment on cardiac pathology and function. Our results showed sunitinib treatment reduced STAT3 phosphorylation in the heart muscle of mdx mice, improved cardiac electrical function, increased cardiac output and stroke volume, decreased ventricular hypertrophy, reduced cardiomyocytes membrane damage, fibrotic tissue deposition and slightly decreased cardiac inflammation. Together, our studies support the idea that sunitinib could serve as a novel treatment to slow cardiomyopathy progression in DMD. One Sentence Summary In this study, we determined if sunitinib, a Food and Drug Administration-approved drug, could reduce the pathology and improve cardiac function in an animal model for DMD.

Dataset Information

Dwarf Open Reading Frame (DWORF) Gene Therapy Ameliorated Duchenne Muscular Dystrophy Cardiomyopathy in Aged mdx Mice.

Publications

Dwarf Open Reading Frame (DWORF) Gene Therapy Ameliorated Duchenne Muscular Dystrophy Cardiomyopathy in Aged mdx Mice.

Similar Datasets

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