Abstract
Sarcolipin (SLN) is an inhibitor of sarco/endoplasmic reticulum (SR) Ca
-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
(Ca
) handling and prevents cardiomyopathy in the
mouse model of DMD. Wild-type,
, SLN-haploinsufficient
(
), and SLN-deficient
(
) mice were used for this study. SERCA function and Ca
handling were determined by Ca
uptake assays and by measuring single-cell Ca
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
mice were determined by RNA-Seq analysis. SERCA function and Ca
cycling were improved in the ventricles of
mice. Fibrosis and necrosis were significantly decreased, and cardiac function was enhanced in the
mice until the study endpoint. The
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
mice. Our findings suggest that reducing SLN expression is sufficient to improve cardiac SERCA function and Ca
cycling and prevent cardiomyopathy in
mice.
First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca
uptake and intracellular Ca
handling and prevents cardiomyopathy in
mice. Second, reducing SLN expression prevents diastolic dysfunction and improves cardiac contractility in
mice Third, reducing SLN expression activates apelin-mediated cardioprotective signaling pathways in
heart.