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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]

Sarcolipin (SLN) is an inhibitor of sarco/endoplasmic reticulum (SR) Ca 2+ -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 Ca 2+ (Ca 2+ i ) handling and prevents cardiomyopathy in the mdx mouse model of DMD. Wild-type, mdx , SLN-haploinsufficient mdx ( mdx:sln +/- ), and SLN-deficient mdx ( mdx:sln -/- ) mice were used for this study. SERCA function and Ca 2+ i handling were determined by Ca 2+ uptake assays and by measuring single-cell Ca 2+ 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 Ca 2+ 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:sln +/- 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 Ca 2+ i cycling and prevent cardiomyopathy in mdx mice. NEW & NOTEWORTHY First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca 2+ uptake and intracellular Ca 2+ handling and prevents cardiomyopathy in mdx mice. Second, reducing SLN expression prevents diastolic dysfunction and improves cardiac contractility in mdx mice Third, reducing SLN expression activates apelin-mediated cardioprotective signaling pathways in mdx heart.

Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca 2+ -ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C 2 C 12 resulted in decreased SERCA pump activity, reduced SR Ca 2+ load, and increased intracellular Ca 2+ ( Ca i 2+ ) concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective Ca i 2+ cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the Ca i 2+ mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the Ca i 2+ cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.