PDF(Pubmed)
Abstract：
Maintaining the structure of cardiac membranes and membrane organelles is essential for heart function. A critical cardiac membrane organelle is the transverse tubule system (called the t-tubule system) which is an invagination of the surface membrane. A unique structural characteristic of the cardiac muscle t-tubule system is the extension of the extracellular matrix (ECM) from the surface membrane into the t-tubule lumen. However, the importance of the ECM extending into the cardiac t-tubule lumen is not well understood. Dystroglycan (DG) is an ECM receptor in the surface membrane of many cells, and it is also expressed in t-tubules in cardiac muscle. Extensive posttranslational processing and O-glycosylation are required for DG to bind ECM proteins and the binding is mediated by a glycan structure known as matriglycan. Genetic disruption resulting in defective O-glycosylation of DG results in muscular dystrophy with cardiorespiratory pathophysiology. Here, we show that DG is essential for maintaining cardiac t-tubule structural integrity. Mice with defects in O-glycosylation of DG developed normal t-tubules but were susceptible to stress-induced t-tubule loss or severing that contributed to cardiac dysfunction and disease progression. Finally, we observed similar stress-induced cardiac t-tubule disruption in a cohort of mice that solely lacked matriglycan. Collectively, our data indicate that DG in t-tubules anchors the luminal ECM to the t-tubule membrane via the polysaccharide matriglycan, which is critical to transmitting structural strength of the ECM to the t-tubules and provides resistance to mechanical stress, ultimately preventing disruptions in cardiac t-tubule integrity.
摘要：
维持心脏膜和膜细胞器的结构对于心脏功能至关重要。关键的心脏膜细胞器是横管系统（称为t管系统），它是表面膜的内陷。心肌t管系统的独特结构特征是细胞外基质（ECM）从表面膜延伸到t管腔中。然而,ECM延伸到心脏t管腔的重要性尚不清楚。Dystroglycan（DG）是许多细胞表面膜中的ECM受体，它也在心肌的t小管中表达。DG结合ECM蛋白需要广泛的翻译后加工和O-糖基化,并且该结合由称为基质聚糖的聚糖结构介导。导致DG的O-糖基化缺陷的遗传破坏导致具有心肺病理生理学的肌营养不良。这里,我们表明DG对于维持心脏t管结构完整性至关重要。DG的O-糖基化缺陷的小鼠发育出正常的t-小管，但容易受到应激诱导的t-小管损失或切断的影响，从而导致心脏功能障碍和疾病进展。最后,我们在一组仅缺乏基质聚糖的小鼠中观察到类似的应激诱导的心脏t管破坏.总的来说，我们的数据表明，t-小管中的DG通过多糖基质聚糖将管腔ECM锚定到t-小管膜，这对于将ECM的结构强度传输到t管至关重要，并提供抗机械应力，最终防止心脏T管完整性的破坏。
