Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis, 2019, Ritterhoff et al

Andy · Nov 13, 2019

In rats.

Rationale: Hypertrophied hearts switch from mainly using fatty acids (FA) to an increased reliance on glucose for energy production. It has been shown that preserving fatty acid oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte (CM) hypertrophy during cardiac stresses. However, it remains elusive if substrate metabolism regulates CM 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 CMs in a medium containing glucose and mixed chain fatty acids and induced pathological hypertrophy by phenylephrine (PE). PE-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 acetyl-CoA-carboxylase 2 (ACC2) in PE stimulated CMs and in pressure overload induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the anti-hypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in CM 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 CM 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.
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Paywall, https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.315483
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Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis, 2019, Ritterhoff et al

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Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis, 2019, Ritterhoff et al

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