P.314Pharmacological activation of SERCA2a SUMOylation improves cardiac function and pathology in models of Duchenne muscular dystrophy

Abstract

Abnormal calcium overload is a critical pathogenic abnormality of Duchenne muscular dystrophy (DMD). Previously, we demonstrated that the SUMOylation plays an essential role in regulating sarcoplasmic reticulum calcium-ATPase (SERCA2a) pump, a prime target for modulation of cardiac contractility. Furthermore, our group identified a first-in-class SERCA2a SUMOylation enhancing compound, N106. This agent improves contractile dysfunction in a mouse model of heart failure. In this study, we investigated whether N106 treatment can improve DMD-associated cardiac dysfunction and muscle damages. Studies were applied to both dystrophin deficient mdx and utrophin heterozygous mdx (mdx/utrn+/-) mice as murine models for DMD. 16-month-old DMD mice were treated with either N106 (10 mg/kg/day) or vehicle (10% DMSO, 10% Tween-80, 80% Saline) by gavage feeding. At two months of N106 treatment, contractile function (fractional shortening (FS): 46.0% in mdx+N106 vs. 35.2% in mdx+vehicle, p < 0.05), muscle fibrosis, forelimb muscle strength and lifespan were improved as compared to vehicle-treated mdx mice. In a separate set of experiment, mdx/utrn+/- mice showed increased cardiac contractility (FS: 47.9% in mdx/utrn+/- + N106 vs. 40.8% in mdx/utrn+/- + vehicle) and reduced left ventricle chamber enlargement (left ventricle diameter end diastole: 3.14 mm in mdx/utrn+/- + N106 vs. 3.52 mm in mdx/utrn+/- + vehicle) at one month following the N106 administration. Additional benefits such as decreased serum creatine kinase levels and reduced muscle fibrosis were observed in mdx/utrn+/- mice treated with N106. These data suggest that small molecule activator-induced enhancement of SERCA2a SUMOylation might be a novel and promising strategy for treating DMD.