Background and Objective: 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, intracellular Ca²⁺ (Ca²⁺_i) handling, and prevent cardiomyopathy in the mdx mouse model of DMD. Methods: The wildtype, mdx, SLN haploinsufficient mdx (mdx:sln+/-) 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 months old mice. Gene expression changes in the ventricles of mdx:sln+/- mice were determined by RNA-Seq analysis. Results: 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: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. Conclusions: Our findings suggest that reducing SLN expression is sufficient to improve cardiac SERCA function and Ca²⁺_i cycling and prevent cardiomyopathy in mdx mice.

中文翻译：

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Sarcolipin 单倍剂量不足可预防 mdx 小鼠的营养不良性心肌病

背景与目的：肌脂蛋白 (SLN) 是一种肌/内质网 (SR) Ca ²⁺ ATP 酶 (SERCA)的抑制剂，在杜氏肌营养不良症 (DMD) 动物模型和患者的心室中高水平表达。本研究的目的是确定 SLN 表达的种系消融是否能改善心脏 SERCA 功能、细胞内 Ca ²⁺ (Ca ²⁺ _i ) 处理，并预防 DMD 的 mdx 小鼠模型中的心肌病。方法：本研究使用野生型、mdx、SLN 单倍体不足 mdx (mdx:sln+/-) 和 SLN 缺陷 mdx (mdx:sln-/-) 小鼠。SERCA 功能和 Ca ²⁺ _i处理通过 Ca ²⁺摄取测定和测量单细胞 Ca 来确定分别为²⁺瞬变。通过组织病理学检查和超声心动图在 6、12 和 20 个月大的小鼠中确定与年龄相关的疾病进展。通过 RNA-Seq 分析确定 mdx:sln+/- 小鼠心室中的基因表达变化。结果：SERCA 函数和 Ca ²⁺ _imdx:sln+/- 小鼠心室的循环得到改善。mdx:sln+/- 小鼠的纤维化和坏死显着减少，心脏功能增强，直到研究终点。mdx:sln-/- 小鼠也表现出类似的有益效果。RNA-Seq 分析确定了不同的基因表达变化，包括 mdx:sln+/- 小鼠心室中 apelin 通路的激活。结论：我们的研究结果表明，降低 SLN 表达足以改善心脏 SERCA 功能和 Ca ²⁺ _i循环并预防 mdx 小鼠的心肌病。