Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
JCI Insight. 2024 Apr 2;9(9):e170185. doi: 10.1172/jci.insight.170185.
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.
杜氏肌营养不良症（DMD）是一种进行性肌肉消耗疾病，常伴有心肌病。DMD 心肌病的特征是细胞内 Ca2+ 稳态异常和线粒体功能障碍。我们使用肌聚糖和肌联蛋白双重敲除（mdx:utrn-/-）小鼠在肌联蛋白（SLN）杂合敲除（sln+/-）背景下，研究 SLN 减少对营养不良心肌中线粒体功能的影响。SLN 表达在 mdx:utrn-/- 小鼠中的种系减少改善了心脏肌浆网（SR）Ca2+循环，减少了心脏纤维化，并改善了心脏功能。在细胞水平上，减少 SLN 的表达可防止线粒体 Ca2+超载，减少线粒体膜电位损失，并改善线粒体功能。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表明，减少 SLN 的表达改善了营养不良心肌细胞中线粒体的结构和 SR-线粒体相互作用。这些发现表明，SLN 的上调在心肌病的发病机制中起着重要作用，减少 SLN 的表达对 DMD 心肌病的治疗具有临床意义。
