mTORC1 调节的代谢受 TSC2 控制，可限制心脏再灌注损伤。
MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury.
机构信息
Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, Berlin, Germany, and German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany (C.U.O.).
Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.).
出版信息
Circ Res. 2021 Mar 5;128(5):639-651. doi: 10.1161/CIRCRESAHA.120.317710. Epub 2021 Jan 6.
RATIONALE
The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis and is activated following ischemia reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little reported. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied before ischemic stress. This can be circumvented by regulating one serine (S1365) on TSC2 (tuberous sclerosis complex) to achieve bidirectional mTORC1 modulation but only with TCS2-regulated costimulation.
OBJECTIVE
We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and is required for IPC by amplifying mTORC1 activity to favor glycolytic metabolism.
METHODS AND RESULTS
Mice with either S1365A (TSC2; phospho-null) or S1365E (TSC2; phosphomimetic) knockin mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2 mice had amplified mTORC1 activation and improved heart function compared with wild-type and TSC2 hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2 hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acylcarnitine levels declined during ischemia. The relative IR protection in TSC2 was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in wild type and TSC2 but not TSC2 which had the worst post-IR function under these conditions.
CONCLUSIONS
TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC. Graphic Abstract: A graphic abstract is available for this article.
原理
mTORC1（雷帕霉素靶蛋白复合物 1）控制代谢和蛋白质稳态，在缺血再灌注（IR）损伤和缺血预处理（IPC）后被激活。然而，关于这种激活是有益还是有害的研究结果存在差异，其对 IR 后代谢的影响报道较少。先前研究的一个局限性是它们使用 mTORC1 功能的广泛增益/损失，主要应用于缺血应激之前。这可以通过调节 TSC2（结节性硬化复合物）上的一个丝氨酸（S1365）来实现双向 mTORC1 调节，但仅在 TCS2 调节的共刺激下才能实现。
目的
我们测试了以下假设，即减少 TSC2 S1365 磷酸化可保护心肌免受 IR 损伤，并通过放大 mTORC1 活性来促进糖酵解代谢，从而对 IPC 是必需的。
方法和结果
研究了具有 S1365A（TSC2；磷酸化缺失）或 S1365E（TSC2；磷酸化模拟）基因突变的小鼠的离体和体内情况。在 IR 反应中，与野生型和 TSC2 心脏相比，TSC2 小鼠的 mTORC1 激活增强，心脏功能改善。保护的程度与 IPC 相匹配。IPC 需要较少的 S1365 磷酸化，因为 TSC2 心脏没有获益，并且不能通过 IPC 激活 mTORC1。IR 代谢在 TSC2 中发生改变，在肌细胞缺氧再灌注后，线粒体耗氧量和糖酵解能力（应激/最大细胞外酸化）增加。在整个心脏中，在缺血期间乳酸增加，长链酰基辅酶 A 水平下降。当在灌注液中降低葡萄糖 36%时，TSC2 中的相对 IR 保护作用丧失。添加脂肪酸（棕榈酸）补偿了野生型和 TSC2 的葡萄糖降低，但不能补偿 TSC2 的葡萄糖降低，在这些条件下，TSC2 的心脏在 IR 后功能最差。
结论
TSC2-S1365 磷酸化状态调节心肌底物利用，其下降激活 mTORC1，使代谢偏向糖酵解而不是脂肪酸氧化，从而提供对 IR 的保护。该途径也被激活，减少 TSC2 S1365 磷酸化是有效 IPC 所必需的。
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