Impact and regulation of lactate metabolism in the heart

心脏乳酸代谢的影响和调节

• 批准号: 10644911
• 负责人: Ahmad A Cluntun
• 金额: $ 11.07万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644911
• 关键词: Address; Adult; Affect; Biochemistry; Bioenergetics; Biology; Carbon; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiac health; Cardiomyopathies; Cells; Cellular Metabolic Process; Chemicals; Citric Acid Cycle; Clinical Research; Coenzyme A; Complex; Congestive Heart Failure; Consumption; Coupled; Cultured Cells; Cytoplasm; DNA Sequence Alteration; Data; Development; Disease; Environment; Environmental Risk Factor; Enzymes; Equilibrium; Generations; Genes; Genetic Models; Glucose; Glycolysis; Health; Heart; Heart Hypertrophy; Heart Transplantation; Heart failure; Heart-Assist Devices; Histones; Homeostasis; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Inherited; Intervention; Isotopes; Left ventricular structure; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Morbidity - disease rate; Mus; Mutation; Myocardial; Myocardium; Operative Surgical Procedures; Oxidative Phosphorylation; Pathogenicity; Pathologic; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Production; Publishing; Pyruvate; Recovery; Regulation; Reporting; Research; Role; Signal Transduction; System; Systolic heart failure; Testing; Therapeutic; Tissue Sample; Tracer; Waste Products; Work; aorta constriction; blood pump; defined contribution; experimental study; extracellular; heart dimension/size; heart function; histone modification; implantation; inhibitor; left ventricular assist device; mortality; mouse model; new therapeutic target; non-histone protein; novel; novel therapeutic intervention; oxidation; pressure; programs; response; stable isotope; transcriptomics; ventricular assist device

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.

项目摘要/摘要 心脏具有独特的新陈代谢，可支持血液的连续泵送。这包括维护 丙酮酸乳酸轴。 该代谢轴描述了三个关键代谢节点之间的相互关系： 细胞质中的中央碳代谢，线粒体中的氧化磷酸化和乳酸 细胞外环境中的丰富性。 在心力衰竭期间，这种代谢轴因增加而失去了不平衡 糖酵解通量与丙酮酸氧化减少并增加乳酸出口。在新发布的数据中，我 证明抑制心脏中的乳酸出口足以重新平衡此轴并减轻心脏 小鼠肥大和心力衰竭。表明将乳酸留在心脏内对其健康有益。 健康的心脏是乳酸的净消费者，这进一步支持了这一点。然而，乳酸代谢 在心脏内部仍然不确定且研究不足。该建议旨在定量地表征乳酸 心脏中的代谢并检验心肌乳酸产生和消耗的假设是不可或缺的 通过在心脏中平衡和维持丙酮酸乳酸轴来进行心脏健康。在我的K99 AIM 1中，我将使用 在正常心肌细胞和心脏中量化乳酸产生和消耗通量的同位素示踪剂。在 我的K99 AIM 2，我将定义慢性心力衰竭患者丙酮酸乳酸轴的代谢重新布线 接受左心室辅助装置（LVAD）疗法，并注入13C-葡萄糖并进行比较 失败和恢复人类的心。我还将用13c-葡萄糖注入HF鼠标模型，并用 MCT4抑制剂VB124，以确定VB124是否是LVAD HF患者的合适治疗方法。在我的R00 AIM3中， 我将构建一个研究计划，围绕全面了解乳酸代谢的方式 受调节及其如何影响肥厚的心肌病（HCM）。总的来说，这些实验将放置 靶向乳酸代谢作为心脏肥大和心脏的新治疗方法的基础 失败。在我的主要导师，同事和我的合作者团队的指导下 期间，该建议将使我能够成功地从当前的指导职位过渡到 独立研究小组负责人。