Lyu Yankun, Verma Vipin K, Lee Younjee, Taleb Iosif, Badolia Rachit, Shankar Thirupura S, Kyriakopoulos Christos P, Selzman Craig H, Caine William, Alharethi Rami, Navankasattusas Sutip, Seidel Thomas, Drakos Stavros G, Sachse Frank B
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
NPJ Aging Mech Dis. 2021 May 28;7(1):16. doi: 10.1038/s41514-021-00066-7.
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.
衰老的心脏会逐渐向衰老表型重塑，这一点已得到充分证实，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。在此，我们表明，心肌细胞中的横管系统（t-系统）以及兴奋-收缩偶联相关蛋白会随着年龄增长发生特征性重塑。我们揭示了这种重塑的机制，并确定了与慢性HF的异同。利用19至75岁供体和HF患者的左心室心肌，我们建立了一个t-系统以及兰尼碱受体（RyR）和连接蛋白2（JPH2）簇的三维重建文库。衰老的特征是t-系统改变和RyR簇的肌膜解离。这种重塑不如HF明显，并伴有JPH2排列的主要改变。我们的研究表明，针对JPH2的肌膜结合可能改善与年龄相关的心脏功能缺陷。
