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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 1

Sarcospan overexpression improves cardiac histology in DMD mouse models.

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Sarcospan overexpression improves cardiac histology in DMD mouse models....
(A) Indirect immunofluorescence detection of SSPN antibody staining of whole heart cryosections from WT, mdx, and mdx:utr-het (mdx:utr+/–) mice and SSPN-overexpressing SSPN-Tg (mdxTG and mdx:utr+/–Tg) mice. Staining represents both endogenous and Tg SSPN expression in hearts of indicated genotypes (n = 4). Scale bar: 900 μm. (B) Masson’s trichrome (MT) staining reflects collagen abundance in transverse whole cardiac cross sections from indicated genotypes (n = 3). Original magnification, ×10 (whole heart images). Scale bar: 900 μm. (C) MT-stained transverse cardiac cross sections (n = 3 biological replicates per genotype). Original magnification, ×20. Scale bar: 50 μm. (D) Quantification of the percentage of fibrotic area in transverse cardiac cross sections determined by analysis of MT collagen staining relative to total area. Data presented are from individual animals, and data are presented as mean ± SEM (n = 3). (E) Intensity of sarcolemma SSPN staining is quantified from immunofluorescence images (n = 3 biological replicates, n = 6 technical replicates), and data are presented as mean ± SEM. For all data shown statistics were determined by 1-way ANOVA followed by Tukey’s multiple comparisons test. P ≤ 0.05 was considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. (F) Transverse whole cardiac cryosections stained with SSPN antibodies reveal robust SSPN expression achieved in mdx hearts upon systemic administration of AAV6 SSPN (n = 3). Scale bar: 900 μm.

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