Title: Recruitment of Sarcolemma Proteins by Sarcospan Rescues Duchenne Muscular Dystrophy Associated Cardiomyopathy
In the current preclinical study, we demonstrate the therapeutic potential of sarcospan (SSPN) to alleviate human cardiomyopathy associated with Duchenne muscular dystrophy (DMD) by utilizing dystrophin-deficient utrophin-haploinsufficient mdx:utr+/- mice 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; upregulated in DMD as a partial compensatory mechanism, however reported to be less efficient in humans. To test the unknown therapeutic efficacy of enhanced SSPN expression on human DMD disease, we examined dependence of SSPN rescue of cardiac function and tissue pathology, on utrophin upregulation. SSPN transgenic overexpression improves systolic performance and hypertrophic indices in baseline echocardiographic studies of mdx and mdx:utr+/- mice and hemodynamic pressure-volume measurements of mdxTG mice compared to mdx controls. SSPN overexpression restores cardiac sarcolemma stability, the primary defect in DMD disease, reduces fibrotic response and improves contractile function in both mdx and mdx:utr+/- mice. We demonstrate that SSPN ameliorates more advanced mdx:utr+/- cardiac disease in context of diminished sarcolemma expression of utrophin and β1D integrin that mitigate disease severity, in addition to partially restoring β-adrenergic responsiveness. Protection afforded to dystrophin-deficient membranes in SSPN-transgenic mice may also be attributed to enhanced abundance of fully glycosylated a-dystroglycan. Overall, this study establishes that SSPN overexpression improves cell membrane stability and cardiac performance, differentiated from our previous findings that suggested that SSPN rescue of DMD-cardiomyopathy largely depends on utrophin upregulation. The significance of this study is that it provides the first evidence that enhancing SSPN expression may provide an important membrane stabilizing role in human DMD disease mouse models positively impacts skeletal, pulmonary and cardiac performance without robust utrophin upregulation, supporting SSPN and membrane stabilization as a target for DMD.