Impact and regulation of lactate metabolism in the heart

项目摘要/摘要 心脏有一种独特的新陈代谢，支持血液的持续泵送。这包括维护 丙酮酸-乳酸轴。 这个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 细胞外环境中的丰度。 在心力衰竭期间，这个代谢轴是不平衡的， 糖酵解助剂与减少丙酮酸氧化和增加乳酸输出有关。在最新公布的数据中，我 证明了抑制心脏中乳酸的输出足以重新平衡这一轴并缓解心脏 小鼠的肥大和心力衰竭。这表明，在心脏内保留乳酸对其健康有益。 健康的心脏是乳酸的净消费者，这一事实进一步支持了这一点。然而，乳酸代谢 仍然没有明确的定义，在内心也没有得到充分的研究。这项提议试图定量描述乳酸盐。 心脏中的代谢，并检验心肌乳酸产生和消耗是不可分割的假设 通过平衡和维持心脏中的丙酮酸-乳酸轴来促进心脏健康。在我的K99目标1中，我将使用 用于量化正常心肌细胞和心脏中乳酸产生和消耗通量的同位素示踪剂。在……里面 我的K99目标2，我将定义慢性心力衰竭患者丙酮酸-乳酸轴的代谢重新连接 输注~(13)C-葡萄糖的左心室辅助装置(LVAD)治疗与对照 心力衰竭和恢复人类心脏。我还会给HF小鼠模型注射13C-葡萄糖，并用 MCT4抑制剂VB124，以确定VB124是否适合治疗LVAD心衰患者。在我的R00 Aim3里， 我将建立一个研究项目，以全面了解乳酸代谢是如何 以及它对肥厚型心肌病(HCM)的影响。总的来说，这些实验将为 靶向乳酸代谢作为治疗心肌肥厚和心脏疾病的新方法的基础 失败了。在K99期间，在我的主要导师、联合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.