Background:The p.(Arg14del) pathogenic variant (R14del) of the PLN (phospholamban) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model.Methods:We investigated the progression of cardiomyopathy in PLN-R14^Δ/Δ mice using echocardiography, ECG, and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 (before the onset of disease), 5 (mild cardiomyopathy), and 8 (end stage) weeks of age. Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del–related cardiomyopathy.Results:At 3 weeks of age, PLN-R14^Δ/Δ mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onward, ventricular dilatation, decreased contractility, and diminished ECG voltages were observed. PLN protein aggregation was present before onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodeling, inflammation, and metabolic dysfunction, in part, similar to ischemic heart disease. Altered protein homeostasis pathways were identified exclusively in PLN-R14^Δ/Δ mice, even before disease onset, in concert with aggregate formation.Conclusions:We mapped the development of PLN-R14del–related cardiomyopathy and identified alterations in proteostasis and PLN protein aggregation among the first manifestations of this disease, which could possibly be a novel target for therapy.

中文翻译：

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蛋白质聚集是 Phospholamban p.(Arg14del) 相关心肌病的早期表现：PLN-R14del 相关心肌病的发展

背景： PLN （受磷蛋白）基因的 p.(Arg14del) 致病性变异 (R14del)是导致心力衰竭心肌病的常见原因。确切的潜在病理生理学尚不清楚，并且没有合适的治疗方法。我们的目标是在临床相关的 PLN-R14del 小鼠模型中确定这种心肌病的分子扰动。方法：我们研究了 PLN-R14 ^{Δ/Δ中心肌病的进展}小鼠使用超声心动图、心电图和组织学组织分析。在 3 周（发病前）、5 周（轻度心肌病）和 8 周（终末期）对心脏组织进行 RNA 测序和质谱分析。将数据与接受心肌缺血再灌注或心肌梗塞手术的小鼠的心脏表达水平进行比较，以努力确定特定于 PLN-R14del 相关心肌病的改变。结果：在 3 周龄时，PLN-R14 ^{Δ/ Δ}小鼠心脏功能正常，但从 4 周龄开始，我们观察到心肌纤维化增加和整体纵向应变受损。从 5 周起，观察到心室扩张、收缩力降低和心电图电压降低。在功能缺陷发作之前存在 PLN 蛋白聚集。转录组学和蛋白质组学揭示了参与重塑、炎症和代谢功能障碍的过程的不同调节，部分类似于缺血性心脏病。仅在 PLN-R14 ^{Δ/Δ中鉴定出改变的蛋白质稳态途径}小鼠，甚至在疾病发作之前，与聚集体形成一致。结论：我们绘制了 PLN-R14del 相关心肌病的发展图，并确定了这种疾病的最初表现中蛋白质稳态和 PLN 蛋白聚集的改变，这可能是一个新的目标用于治疗。