Perino Maria Grazia, Calvo-Rubio Barrera Miguel, Riordon Daniel R, Agnetti Giulio, Maltsev Alexander, Parveen Admira, Morrell Christopher H, Ahmet Ismayil, Chakir Khalid, Tarasova Yelena S, Qu Jia-Hua, Tarasov Kirill V, Lyashkov Alexey E, Lukyanenko Yevgeniya O, Kadioglu Hikmet, Ranek Mark, De Cabo Rafael, Lakatta Edward G
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute On Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Translational Gerontology Branch, Intramural Research Program, National Institute On Aging, National Institutes of Health, Baltimore, MD, USA.
Geroscience. 2025 Sep 1. doi: 10.1007/s11357-025-01851-y.
Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VIII (TG). We assessed protein quality control mechanisms (PQC) (ubiquitin proteasome system, autophagic flux via macroautophagy, and mitophagy) in left ventricles of TG and wild-type littermates (WT) at 3-4 and 17-21 months of age. At 3-4 months, TG exhibited markers of increased autophagic flux (microtubule-associated protein 1A/1B light chain 3B (LC3), p62, and their phospho-forms) and enhanced canonical mitophagy signaling (PARKIN, p62 and p62 receptors), confirming a more efficient proteostasis, vs WT. In aged TG, however, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity, slower autophagic flux, and increased mitochondrial dysfunction (network fragmentation). The accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions), of lipofuscin bodies and of desmin cardiac preamyloid oligomers, and of LC3- and p62-inclusions of aberrant sizes was increased in aged TG compared to young TG. Thus, while increased proteostatic mechanisms maintain cardiac health in TG in youth (3-4 months), long-term exposure to sustained activation of the AC/cAMP/PKA/Ca signaling axis results in severe proteostasis insufficiency in aged TG, leading to cardiomyopathy and accelerated cardiac aging.
蛋白质稳态失调是衰老的一个标志。我们研究了在心脏特异性显著过表达腺苷酸环化酶VIII（TG）的小鼠中，随着年龄增长，蛋白质稳态对慢性心脏环磷酸腺苷（cAMP）依赖性应激的适应性变化效率如何。我们评估了3 - 4个月和17 - 21个月大的TG小鼠和野生型同窝小鼠（WT）左心室中的蛋白质质量控制机制（PQC）（泛素蛋白酶体系统、通过巨自噬的自噬通量和线粒体自噬）。在3 - 4个月时，与WT相比，TG表现出自噬通量增加的标志物（微管相关蛋白1A/1B轻链3B（LC3）、p62及其磷酸化形式）和经典线粒体自噬信号增强（帕金蛋白、p62和p62受体），证实其蛋白质稳态更有效。然而，在老年TG小鼠中，PQC机制被蛋白毒性应激 overwhelm，表现为蛋白酶体活性不足、自噬通量减慢和线粒体功能障碍增加（网络碎片化）。与年轻TG相比，老年TG中蛋白质聚集体（不溶性/可溶性蛋白质组分比例增加）、脂褐质体、结蛋白心脏淀粉样前体寡聚物以及异常大小的LC3和p62包涵体的积累增加。因此，虽然增加的蛋白质稳态机制在年轻时（3 - 4个月）维持了TG小鼠的心脏健康，但长期暴露于AC/cAMP/PKA/Ca信号轴的持续激活会导致老年TG小鼠出现严重的蛋白质稳态不足，从而导致心肌病和心脏衰老加速。
