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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 4

SSPN improvement of cardiac performance in DMD mice cannot be attributed to utrophin upregulation.

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SSPN improvement of cardiac performance in DMD mice cannot be attributed...
(A) Confocal immunofluorescence images of transverse cross sections of WT, mdx, mdxTG hearts (original magnification, ×20). To assess levels of major structural proteins associated with DMD, antibodies were utilized for dystrophin (Dys), utrophin (Utr), and Itgb (β1D integrin). Confocal settings were as follows: gain, 746.0 m/s, offset –0.30%; gain 788.6 m/s, offset –0.30%; gain 779.3 m/s, offset –0.50%, respectively. Expression of key DGC proteins important in stabilization and connection with laminin in the extracellular matrix (ECM) was assessed for α-dystroglycan (α-DG), core-DG (45-3), and β-dystroglycan (β-DG). Confocal settings were as follows: gain 733.6 m/s, offset –0.10%; gain: 819.5 m/s, offset –0.30%; gain 787.7 m/s, offset –0.40%, respectively. Sarcoglycans were upregulated at the DMD sarcolemma in hearts overexpressing SSPN. Antibodies utilized were specific for α-sarcoglycan (α-SG), β-sarcoglycan (β-SG), and γ-sarcoglycan (γ-SG). Scale bar: 50 μm. Confocal setting information is as follows: α-SG — gain 630.1 m/s, offset –0.50%; β-SG — gain 719.5 m/s, offset –1.80%; γ-SG — gain 721.3 m/s, –0.40% (n = 3 for each antibody and genotype). (B) Confocal immunofluorescence images of utrophin staining, Original magnification, ×63. Confocal settings were as follows: gain 788.6 m/s, offset –0.10%. Scale bar: 100 μm. (C) Intensity of sarcolemma protein staining of utrophin, Itgb, α-DG (IIH6), and α-SG is quantified from immunofluorescence images and all groups were compared by 1-way ANOVA using Tukey’s multiple comparison test (n = 3 biological replicates, n = 6 analyzed images). Data are presented as mean ± SEM. P ≤ 0.05 was considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

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