衰老与心脏衰竭中t系统的重塑和兴奋-收缩耦合背后的蛋白质。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY NPJ Aging and Mechanisms of Disease Pub Date : 2021-05-28 DOI:10.1038/s41514-021-00066-7
Yankun Lyu, Vipin K Verma, Younjee Lee, Iosif Taleb, Rachit Badolia, Thirupura S Shankar, Christos P Kyriakopoulos, Craig H Selzman, William Caine, Rami Alharethi, Sutip Navankasattusas, Thomas Seidel, Stavros G Drakos, Frank B Sachse
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引用次数: 5

摘要

众所周知,衰老的心脏会逐渐重塑为衰老表型,但细胞微观结构的改变及其与慢性心力衰竭(HF)相关重塑的差异仍不明确。在这里,我们发现心肌细胞中的横管系统(t系统)和兴奋-收缩耦联的蛋白质随着年龄的增长而特征重塑。我们阐明了这种重塑的机制,并确定了与慢性心衰的异同。使用捐赠者和年龄在19 - 75岁之间的HF患者的左心室心肌,我们建立了t系统以及ryanodine受体(RyR)和junctophilin 2 (JPH2)簇的3D重建库。衰老的特征是t系统的改变和RyR簇的肌上皮解离。与HF相比,这种重塑不那么明显,并伴有JPH2排列的重大改变。我们的研究表明,靶向JPH2的肌层关联可能会改善与年龄相关的心功能缺陷。
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Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart.

It is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
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8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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