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Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy
Michelle S. Parvatiyar, … , Jose Renato Pinto, Rachelle H. Crosbie
Michelle S. Parvatiyar, … , Jose Renato Pinto, Rachelle H. Crosbie
Published April 30, 2019
Citation Information: JCI Insight. 2019;4(11):e123855. https://doi.org/10.1172/jci.insight.123855.
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Research Article Cardiology Muscle biology

Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy

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Abstract

In the current preclinical study, we demonstrate the therapeutic potential of sarcospan (SSPN) overexpression to alleviate cardiomyopathy associated with Duchenne muscular dystrophy (DMD) utilizing dystrophin-deficient mdx mice with utrophin haploinsufficiency that more accurately represent the severe disease course of human DMD. SSPN interacts with dystrophin, the DMD disease gene product, and its autosomal paralog utrophin, which is upregulated in DMD as a partial compensatory mechanism. SSPN-Tg mice have enhanced abundance of fully glycosylated α-dystroglycan, which may further protect dystrophin-deficient cardiac membranes. Baseline echocardiography revealed that SSPN improves systolic function and hypertrophic indices in mdx and mdx:utr-heterozygous mice. Assessment of SSPN-Tg mdx mice by hemodynamic pressure-volume methods highlighted enhanced systolic performance compared with mdx controls. SSPN restored cardiac sarcolemma stability, the primary defect in DMD disease; reduced fibrotic response; and improved contractile function. We demonstrate that SSPN ameliorated more advanced cardiac disease in the context of diminished sarcolemma expression of utrophin and β1D integrin, which mitigate disease severity, and partially restored responsiveness to β-adrenergic stimulation. Overall, our current and previous findings suggest that SSPN overexpression in DMD mouse models positively affects skeletal, pulmonary, and cardiac performance by addressing the stability of proteins at the sarcolemma that protect the heart from injury, supporting SSPN and membrane stabilization as a therapeutic target for DMD.

Authors

Michelle S. Parvatiyar, Alexandra J. Brownstein, Rosemeire M. Kanashiro-Takeuchi, Judd R. Collado, Karissa M. Dieseldorff Jones, Jay Gopal, Katherine G. Hammond, Jamie L. Marshall, Abel Ferrel, Aaron M. Beedle, Jeffrey S. Chamberlain, Jose Renato Pinto, Rachelle H. Crosbie

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Figure 7

Sarcospan overexpression provides system-wide correction of DMD muscle pathology.

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Sarcospan overexpression provides system-wide correction of DMD muscle p...
A schematic illustration depicts the major therapeutic benefits of SSPN overexpression in DMD-associated cardiomyopathy based on our preclinical studies in several relevant DMD murine models. Areas of improvement in the DMD-associated cardiomyopathy disease course are marked with blue asterisks. SSPN overexpression has many beneficial effects, as highlighted, including enhancing systolic function and prevention of ventricular remodeling. These positive outcomes are mediated primarily by stabilizing the cell membrane subsequently protecting against cardiomyocyte loss and downstream consequences, including fibrosis and cardiac dysfunction. A schematic of the protein complexes affected by SSPN overexpression is also shown, which protects the myocardium. Improvements in cell membrane stability result in lower EBD uptake in cardiac muscle, reduced muscle/cardiac creatine kinase leakage into the blood, and decreased fibrosis. The overall ability of SSPN to increase abundance of β1D integrin, sarcoglycans, dystroglycans and perhaps utrophin enhance cardiomyocyte sarcolemma stability and protect against functional decline and tissue damage.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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