Impact and regulation of lactate metabolism in the heart

项目总结/摘要 心脏有一个独特的新陈代谢，支持血液的持续泵送。这包括维护 乳酸-乳酸轴。 该代谢轴描述了三个关键代谢节点之间的相互关系： 细胞质中的中心碳代谢、线粒体中的氧化磷酸化和乳酸 在细胞外环境中的丰度。 在心力衰竭期间，该代谢轴由于增加的 糖酵解通量与降低的丙酮酸氧化和增加的乳酸输出偶联。在新公布的数据中，我 证明抑制心脏中的乳酸输出足以重新平衡该轴并减轻心脏 肥大和心力衰竭。这表明在心脏内保留乳酸盐对心脏健康有益。 健康的心脏是乳酸盐的净消费者这一事实进一步支持了这一点。然而，乳酸代谢 在心脏中仍然定义不清，研究不多。该提案旨在定量表征乳酸盐 心脏中的代谢，并测试心肌乳酸产生和消耗是不可或缺的假设， 通过平衡和维持心脏中的乳酸盐-乳酸盐轴来促进心脏健康。在K99 Aim 1中，我将使用 同位素示踪剂，以量化正常心肌细胞和心脏中的乳酸产生和消耗通量。在 我的K99目标2，我将定义慢性心力衰竭患者的乳酸-乳酸轴的代谢重新布线 接受左心室辅助装置（LVAD）治疗，并输注13 C-葡萄糖， 使人的心脏衰竭并恢复我还将用13 C-葡萄糖输注HF小鼠模型，并用 MCT 4抑制剂VB 124，以确定VB 124是否是LVAD HF患者的合适治疗。在我的R 00 AIM 3中， 我将建立一个以全面了解乳酸代谢为中心的研究计划 调节，以及它如何影响肥厚型心肌病（HCM）。总的来说，这些实验将奠定 靶向乳酸代谢作为心肌肥大和心脏病新治疗方法的基础 失败在K99期间，在我的主要导师、共同导师和我的合作者团队的指导下， 在此期间，这项建议将使我能够成功地从目前的指导职位过渡到 独立研究小组组长。

Project Summary/Abstract The heart has a distinct metabolism that supports the continuous pumping of blood. This includes maintaining the pyruvate-lactate axis. This metabolic axis describes the interrelation between three critical metabolic nodes: central carbon metabolism in the cytoplasm, oxidative phosphorylation in the mitochondria, and lactate abundance in the extracellular milieu. During heart failure, this metabolic axis is imbalanced by increased glycolytic flux coupled to decreased pyruvate oxidation and increased lactate export. In newly published data, I demonstrated that inhibiting lactate export in the heart, was sufficient to rebalance this axis and mitigate cardiac hypertrophy and heart failure in mice. Suggesting that retaining lactate within the heart is beneficial to its health. This is further supported by the fact that healthy hearts are net consumers of lactate. Yet, lactate metabolism remains ill-defined and poorly studied within the heart. This proposal seeks to quantitatively characterize lactate metabolism in the heart and to test the hypothesis that myocardial lactate production and consumption is integral to cardiac health by balancing and maintaining the pyruvate-lactate axis in the heart. In my K99 Aim 1, I will use isotope tracers to quantify lactate production and consumption fluxes in normal cardiomyocytes and hearts. In my K99 Aim 2, I will define the metabolic rewiring of the pyruvate-lactate axis in chronic heart failure patients undergoing left ventricle assist device (LVAD) therapy that have been infused with 13C-glucose and compare failing and recovering human hearts. I will also infuse HF mouse models with 13C-glucose and treat them with the MCT4 inhibitor VB124, to determine if VB124 is a suitable treatment for LVAD HF patients. In my R00 Aim3, I will build a research program centered around comprehensively understanding how lactate metabolism is regulated, and how it impacts hypertrophic cardiomyopathy (HCM). Collectively, these experiments will lay the groundwork for targeting of lactate metabolism as a new therapeutic approach in cardiac hypertrophy and heart failure. Under the guidance of my primary mentor, Co-mentor and my team of collaborators during the K99 period, this proposal will allow me to successfully transition from my current mentored position into an independent research group leader.