PDF(Pubmed)
Abstract：
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin double-knockout (mdx:utrn-/-) mice in a sarcolipin (SLN) heterozygous-knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes showed that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiomyocytes. These findings indicate that SLN upregulation plays a substantial role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD cardiomyopathy.
摘要：
杜氏肌营养不良症（DMD）是一种与心肌病相关的进行性肌肉萎缩疾病。DMD-心肌病的特征在于细胞内Ca2+稳态异常和线粒体功能障碍。我们在sarcolipin（SLN）杂合子敲除（sln/-）背景中使用了肌营养不良蛋白和utrophinnull（mdx：utrn-/-）小鼠，以检查SLN减少对营养不良心肌线粒体功能的影响。mdx：utrn-/-小鼠中SLN表达的种系减少改善了心脏sarco/内质网（SR）Ca2循环，减少心脏纤维化，和改善心脏功能。在细胞层面,降低SLN表达可预防线粒体Ca2+过载，减少线粒体膜电位损失，和改善线粒体功能。心肌组织的透射电子显微镜和线粒体相关膜的蛋白质组学分析显示，减少SLN表达改善了营养不良心肌细胞的线粒体结构和SR-线粒体相互作用。这些发现表明，SLN上调在心肌病的发病机理中起着重要作用，并且降低SLN表达在DMD-心肌病的治疗中具有临床意义。
