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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 mdx mouse model of DMD. Wild-type, mdx, SLN-haploinsufficient mdx (mdx:slnþ/-), and SLN-deficient mdx (mdx: sln-/-) 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 mdx:sln+/- mice were determined by RNA-Seq analysis. SERCA function and Ca2+ i cycling were improved in the ventricles of mdx:sln+/- mice. Fibrosis and necrosis were significantly decreased, and cardiac function was enhanced in the mdx:slnþ/- mice until the study endpoint. The mdx: sln-/- 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 mdx:sln+/- mice. Our findings suggest that reducing SLN expression is sufficient to improve cardiac SERCA function and Ca2+ i cycling and prevent cardiomyopathy in mdx mice. [ABSTRACT FROM AUTHOR]