Sestrin2抑制mTORC1过度激活改善压力超负荷导致的老年小鼠心肌肥厚

Aging myocardium can easily develop myocardial dysfunction under stress,The biological mechanism of increased vulnerability of aging myocardium needs urgent elucidation. During the aging process, pressure overload can induce myocardial hypertrophy. The mechanism is still unknown. Our previous studies found that Sestrin2 is an important endogenous myocardial protection signal and there is a close relation of decreased Sestrin2 level with vulnerability of aging myocardium. Our recent study showed over-activation of the mTORC1 signal pathway in both aged mice and Sestrin2 KO mice after TAC technique. Sestrin2 KO mice had accelerated aging myocardial phenotype and significantly prominent TAC induced myocardial hypertrophy. However, the specific regulatory mechanism of Sestrin2 on mTORC1 signal remains to be clarified. We speculate that Sestrin2 can directly regulate mTORC1 signal and the decreased Sestrin2 level is involved in process of myocardial hypertrophy in elderly. The aim of this study is to investigate the mechanism of excessive activation of mTORC1 in the aging myocardial hypertrophy by adopting naturally aged mice and Sestrin2 knockout mice models and intervening them with myocardial specific Sestrin2. We also investigate the specific regulatory mechanism of Sestrin2 inhibiting mTORC1. This research is expected to provide new insights and novel prevention targets for aging related myocardial injury.

衰老心肌在应激状态下极易出现心功能障碍，其易损性增加的生物学机制亟待阐明。在增龄过程，压力超负荷极易导致心肌肥厚且机制不明。我们前期研究首先发现：Sestrin2是重要的心肌内源性保护信号，其水平减退与衰老心肌易损性密切相关。我们最新发现：老年小鼠和Sestrin2 KO小鼠TAC术后出现mTORC1信号途径的过度激活。Sestrin2 KO小鼠加速心肌衰老表型；并显著加重TAC导致的心肌肥厚。但是Sestrin2对mTORC1信号的具体调控机制尚待阐明。我们提出：Sestrin2可能直接调控mTORC1信号，Sestrin2水平减退参与老年心肌肥厚的发生。本研究拟通过自然衰老小鼠、Sestrin2敲除小鼠，并采用心肌特异性Sestrin2干预，探讨衰老心肌肥厚过程中mTORC1过度激活机制；Sestrin2抑制mTORC1的具体调控机制。本研究有望为衰老相关的心肌损伤提供新认识防治靶点。

Sestrin2（Sesn2）是哺乳动物雷帕霉素靶蛋白(mTORC1,Mammalian Target of Rapamycin Complex 1)通路的压力传感器。衰老损伤心脏mTORC1的激活，从而使心脏对肥大敏感。C57BL/6J年轻野生型（年轻WT；4-6个月）、老年WT（24-26个月）和年轻Sestrin2敲除小鼠（Y-Sesn2 KO；4-6个）通过横向主动脉收缩（TAC）导致压力过载。TAC后4周，与年轻WT小鼠相比，老年WT和Y-Sesn2 KO表现出更大的心脏和更严重的心脏功能损伤。mTOR和下游底物的磷酸化增强；在老年WT和Y-Sesn2 KO心脏中观察到线粒体受损和氧化还原标记物升高，以及葡萄糖和脂肪酸氧化受损。压力过载诱导Sesn2和GTPase之间的相互作用，这在老年WT心脏中受损正调节mTORC1的功能。腺相关病毒9-Sesn2（AAV9-Sesn2）治疗提高老年WT和Y-Sesn2 KO心脏中Sesn2的表达，减弱了mTORC1的激活，并增加对压力过载耐受性。这些结果表明在心脏Sesn2起mTORC1的压力过载传感器的作用。此外，Sesn2缺乏可能导致老年对肥大的敏感性增加。