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.

众所周知，老化的心脏会逐渐向衰老表型重塑，但细胞微观结构的改变及其与慢性心力衰竭 (HF) 相关重塑的差异仍然不明确。在这里，我们显示横管系统（t-系统）和心肌细胞中激发-收缩耦合基础的蛋白质随着年龄的增长而特征性地重塑。我们阐明了这种重塑的机制，并确定了与慢性 HF 的异同。我们使用年龄在 19 至 75 岁之间的捐赠者和 HF 患者的左心室心肌，建立了 t 系统以及兰尼碱受体 (RyR) 和亲核蛋白 2 (JPH2) 簇的 3D 重建库。衰老的特点是 t 系统改变和 RyR 簇的肌膜分离。这种重塑不如HF明显，并伴有JPH2排列的重大改变。我们的研究表明，靶向 JPH2 的肌膜关联可能会改善与年龄相关的心脏功能缺陷。