Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis

Abstract

Rationale: Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics. Objective: The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes. Methods and Results: We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload–induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy. Conclusions: Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

“…The healthy myocardium predominantly uses fatty acids to sustain ATP synthesis, 37,38 but substrate preference and metabolic flexibility of the heart are altered under pathological conditions 39 . For instance, the switch from fatty acids to glucose during pressure overload remodels metabolic fluxes to support biomass synthesis, thereby contributing to the hypertrophic growth of the heart, and protein O‐GlcNAcylation, thereby contributing to calcium mishandling and cardiac dysfunction 40–43 . Thus, metabolic reprogramming in both cancer cells and cardiomyocytes is directed toward the synthesis of anabolic precursors that are required to support cell proliferation and hypertrophy, respectively.…”

“…Thus, metabolic reprogramming in both cancer cells and cardiomyocytes is directed toward the synthesis of anabolic precursors that are required to support cell proliferation and hypertrophy, respectively. However, important differences in metabolic reprogramming exist between tumours and the heart; for instance, in contrast to cancer cells, cardiomyocytes do not rely on glutamine for aspartate synthesis 40,44 …”

Metabolic Modulation of Macrophage Function Post Myocardial Infarction

“…Besides producing ATP for the cell, mitochondria play multiple regulatory roles in cellular signaling, redox balance, cell growth, and survival (Zhou and Tian, 2018;Ritterhoff et al, 2020). Changes in mitochondrial function have been observed in activated macrophages, but the molecular mechanisms connecting mitochondrial function and macrophage phenotypes are not fully understood.…”

Research Progress on the Interaction Between Autophagy and Energy Homeostasis in Cardiac Remodeling

“…Increased glucose utilization in cardiac hypertrophy promotes aspartate biosynthesis, leading to the increased synthesis of nucleotides, RNA and proteins (Nakamura and Sadoshima, 2018). A deletion of acetyl-CoA-carboxylase2 (ACC2) increases fatty acid oxidation to maintain catabolic metabolism for energy production and avoid anabolic metabolism (Ritterhoff et al, 2020). Indeed, the energy metabolism pattern in cardiac pressure overload-induced cardiac remodeling is similar to the fetal heart, which is characterized by reduced ATP synthesis that leads to inefficient energy metabolism (Sorokina et al, 2007).…”