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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 6

Sarcospan protects dystrophic hearts from β-adrenergic–mediated membrane damage.

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Sarcospan protects dystrophic hearts from β-adrenergic–mediated membrane...
(A) The diagram indicates the isoproterenol-dosing regimen utilized to test whether SSPN overexpression improves responsiveness to β-adrenergic stimulation. The immediate functional effects of β-adrenergic stimulation are reported on heart rate (HR), dP/dtmax, and LV EF% after 2 bolus doses of intravenous isoproterenol: Iso 1 indicates 30 ng/kg and Iso 2 indicates 90 ng/kg for the indicated genotypes. WT (untreated: n = 6, post-Iso n = 6), mdx (untreated: n = 7, post-Iso n = 7), and mdxTG (untreated: n = 7, post-Iso n = 5) mice were monitored before and after isoproterenol treatment by pressure-volume analysis. For WT LV EF% values, measurements before and after isoproterenol were near significance: P ≤ 0.086. Data are presented as individual points from each animal and are presented as mean ± SEM. A summary of values is provided in Table 3. Individual Student’s t test compared the 2 groups (baseline versus isoproterenol-treated mice) for each genotype. (B) Membrane stability was assessed in WT, mdx, mdxTG, mdx:utr-het (mdx:utr+/–), mdx:utr-hetTG (mdx:utr+/–Tg) 12-month-old mice injected with Evan’s blue dye (EBD; red fluorescence) and subjected to an isoproterenol-dosing regime and 3 intraperitoneal injections of 500 ng/g at 18-, 20-, and 22-hour time points. Transverse cardiac cryosections of isoproterenol-treated mice were costained with laminin antibodies (green fluorescence) and visualized by indirect immunofluorescence microscopy. Scale bar: 50 μm (top); 900 μm (bottom) (n = 4, each genotype). (C) Quantification of EBD uptake is reported in untreated (-) and isoproterenol-treated (+) WT (n = 4), mdx (n = 5), mdxTG (n = 4), mdx:utr-het (mdx:utr+/–) (n = 4), mdx:utr-hetTG (mdx:utr+/–Tg) (n = 6) mice (n = 2 technical replicates). The percentage of EBD-positive area was calculated and reported for the above samples as a percentage relative to total tissue area (top). The total number of EBD-positive areas was also reported in the samples (bottom). Data are presented as individual points, and data are presented as mean ± SEM. (D) Cardiac-specific creatine kinase (CK-MB) levels in the blood serum of 14-month-old untreated WT (n = 3), mdx (n = 3), mdxTG (n = 5), mdx:utr-het (mdx:utr+/–) (n = 3), mdx:utr-hetTG (mdx:utr+/–Tg) (n = 3) mice. Results from each animal are plotted as individual points, and data are presented as mean ± SEM. Data reported in C and D were compared by 1-way ANOVA utilizing Tukey’s multiple comparison test. P ≤ 0.05 was considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

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