蛋白质降解功能减退是衰老相关心血管疾病的亚临床基础；细胞自噬和泛素-蛋白酶系统在老年心肌蛋白质降解障碍中的分子联系仍待阐明。我们前期探索发现①衰老心肌自噬溶酶体囊泡融合障碍；②激活AMPK可上调衰老心肌E3泛素连接酶Atrogin-1并改善自噬功能，但机制不明；③反之，心肌特异性敲低Atrogin-1导致autophagy flux障碍；④调控自噬溶酶体囊泡融合的关键蛋白CHMP2B可能是Atrogin-1底物。据此我们提出自噬/UPS协同新机制：“AMPK-Atrogin-1-CHMP2B”轴调控心肌基础自噬；该机制受损导致衰老心肌功能性自噬流障碍。本研究拟通过模式动物及机能研究探讨衰老心肌自噬功能障碍新的调控机制，通过选择性干预实现从自噬诱导到囊泡融合环节联动的功能化自噬流调节。本研究不仅为“亚临床心肌老化”提供新的理解，还为改善衰老心肌自噬能力防治老年相关心血管疾病提供新的干预靶点。

Protein degradation function impairment is the subclinical basis of age-related cardiovascular disease, whereas the molecular mechanisims link between autophagy and ubiquitin/proteasome system under protein degradation disorder in aged heart remains to be elucidated. Our previous work identified that: (1) autophagosome-lysosome fusion was impaired in aged cardiomyocyte. (2) AMPK activation increased the ubiquitin ligases Atrogin-1 expression and consequently enhanced myocardial autophay, but the regulative mechanism remains unknown. (3) Conversely, myocardial specificity Atrogin–1 knockdown causes impairment of autophagy flux. (4) We also found CHMP2B, a key regulator of autophagosome-lysosome fusion, is probably the novel target of Atrogin–1. We hypothesize that AMPK-Atrogin-1-CHMP2B signaling pathway mediates the myocardial autophagy by targeting the cross-talk between the ubiquitin/proteasome system and autophagy system during cardiac aging. Impairment of this signal pathway may result in aging-related autophagic flux disorder. The aim of the project is to enhance our mechanistic understanding of the subclinical myocardial senescence. The present study will provide new therapeutic targets for age-related cardiovascular disease through ameliorating the aurophagy in aged heart.