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Scientific Articles

Stabilization of the Cardiac Sarcolemma by Sarcospan Rescues DMD-Associated Cardiomyopathy

key information

source: JCI Insight

year: 2019

authors: Parvatiyar MS, Brownstein AJ, Kanashiro-Takeuchi RM, Collado JR, Dieseldorff Jones KM, Gopal J, Hammond KG, Marshall JL, Ferrel A, Beedle AM, Chamberlain JS, Renato Pinto J, Crosbie RH

summary/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 transgenic mice have enhanced abundance of fully glycosylated α-dystroglycan, which may further protect dystrophin-deficient cardiac membranes. Baseline echocardiography reveals SSPN improves systolic function and hypertrophic indices in mdx and mdx:utr-heterozygous mice. Assessment of SSPN transgenic mdx mice by hemodynamic pressure-volume methods highlights enhanced systolic performance compared to mdx controls. SSPN restores cardiac sarcolemma stability, the primary defect in DMD disease, reduces fibrotic response and improves contractile function. We demonstrate that SSPN ameliorates more advanced cardiac disease in the context of diminished sarcolemma expression of utrophin and β1D integrin that mitigate disease severity and partially restores responsiveness to β-adrenergic stimulation. Overall, our current and previous findings suggest SSPN overexpression in DMD mouse models positively impacts 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.

organization: UCLA, USA; University of Miami, USA; Florida State University, USA; Binghamton University State University of New York, USA; University of Washington, USA; David Geffen School of Medicine at UCLA, USA

DOI: 10.1172/jci.insight.123855

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