Nanoscale remodeling of ryanodine receptor cluster size underlies cerebral microvascular dysfunction in Duchenne muscular dystrophy

作者：Harry A. T. Pritchard, Paulo W. Pires, Evan Yamasaki, Pratish Thakore, Scott Earley · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1804593115 · 被引用次数：41 · 研究领域：Muscle Physiology and Disorders、Ion channel regulation and function、Mitochondrial Function and Pathology

Significance Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disease that results from mutations in the gene encoding dystrophin. The effects of the disease on cardiac and skeletal muscle have been intensely investigated, but much less is known about how DMD impacts vascular smooth muscle cells (SMCs). Using superresolution nanoscopy, we demonstrate that clusters of ryanodine receptors (RyR2s) on the sarcoplasmic reticulum (SR) of cerebral artery SMCs from the mdx mouse model of DMD are larger compared with controls. Increased RyR2 cluster size is associated with augmented SR Ca 2+ release and Ca 2+ -activated K + channel activity, resulting in impaired vasoconstriction of cerebral microvessels. Our findings demonstrate that remodeling of RyR2 clusters at the molecular level results in cerebral microvascular dysfunction during DMD.