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

Michelle S. Parvatiyar, Alexandra J. Brownstein, Rosemeire 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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1 Scopus citations

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.

Original languageEnglish (US)
Article numbere123855
JournalJCI Insight
Volume4
Issue number11
DOIs
StatePublished - Jun 6 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Parvatiyar, M. S., Brownstein, A. J., Takeuchi, R., Collado, J. R., Dieseldorff Jones, K. M., Gopal, J., Hammond, K. G., Marshall, J. L., Ferrel, A., Beedle, A. M., Chamberlain, J. S., Pinto, J. R., & Crosbie, R. H. (2019). Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy. JCI Insight, 4(11), [e123855]. https://doi.org/10.1172/jci.insight.123855