Sarcolipin haploinsufficiency prevents dystrophic cardiomyopathy in <i>mdx</i> mice

Abstract

Sarcolipin (SLN) is an inhibitor of sarco/endoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA) and expressed at high levels in the ventricles of animal models for and patients with Duchenne muscular dystrophy (DMD). The goal of this study was to determine whether the germline ablation of SLN expression improves cardiac SERCA function and intracellular Ca²⁺ (Ca²⁺_i) handling and prevents cardiomyopathy in the <i>mdx</i> mouse model of DMD. Wild-type, <i>mdx</i>, SLN-haploinsufficient <i>mdx</i> (<i>mdx:sln^+/-</i>), and SLN-deficient <i>mdx</i> (<i>mdx:sln^-/-</i>) mice were used for this study. SERCA function and Ca²⁺_i handling were determined by Ca²⁺ uptake assays and by measuring single-cell Ca²⁺ transients, respectively. Age-dependent disease progression was determined by histopathological examinations and by echocardiography in 6-, 12-, and 20-mo-old mice. Gene expression changes in the ventricles of <i>mdx:sln^+/-</i> mice were determined by RNA-Seq analysis. SERCA function and Ca²⁺_i cycling were improved in the ventricles of <i>mdx:sln^+/-</i> mice. Fibrosis and necrosis were significantly decreased, and cardiac function was enhanced in the <i>mdx:sln^+/-</i> mice until the study endpoint. The <i>mdx:sln^-/-</i> mice also exhibited similar beneficial effects. RNA-Seq analysis identified distinct gene expression changes including the activation of the apelin pathway in the ventricles of <i>mdx:sln^+/-</i> mice. Our findings suggest that reducing SLN expression is sufficient to improve cardiac SERCA function and Ca²⁺_i cycling and prevent cardiomyopathy in <i>mdx</i> mice.<b>NEW & NOTEWORTHY</b> First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca²⁺ uptake and intracellular Ca²⁺ handling and prevents cardiomyopathy in <i>mdx</i> mice. Second, reducing SLN expression prevents diastolic dysfunction and improves cardiac contractility in <i>mdx</i> mice Third, reducing SLN expression activates apelin-mediated cardioprotective signaling pathways in <i>mdx</i> heart.