Impact and regulation of lactate metabolism in the heart

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.