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HEART FAILURE

Rebalancing the pyruvate–lactate axis to treat heart failure

Nature Reviews Cardiology volume 18, pages 150–151 (2021)Cite this article

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New research shows that the pyruvate–lactate axis is an important regulatory node for cardiac homeostasis and function. Ahmad Cluntun and colleagues identify the mitochondrial pyruvate carrier (MPC) and the cell membrane lactate exporter monocarboxylate transporter 4 (MCT4) as crucial regulators of this axis and show that alteration of the pyruvate–lactate axis is an early event in cardiomyocyte hypertrophy and heart failure (HF). “This finding has the potential to open the door to novel therapeutic interventions that specifically target cardiac metabolism to treat HF and induce myocardial recovery,” highlight the investigators.

Next, Cluntun and colleagues confirmed the causal role of the MPC in HF and cardiac recovery in experimental models. Cardiac-specific MPC deficiency in mice caused early cardiac hypertrophy and chronic HF. In isolated cardiomyocytes, loss of MPC was sufficient to induce hypertrophy, whereas MPC overexpression mitigated drug-induced hypertrophy. Finally, the investigators developed a selective MCT4 inhibitor and showed that the activity of MCT4, which metabolically opposes MPC, is required for cardiomyocyte hypertrophy. Treatment with the MCT4 inhibitor attenuated and reversed hypertrophy in isolated cardiomyocytes and in mouse hearts in vivo. MCT4 inhibition restored mitochondrial pyruvate flux, indicating that maintaining mitochondrial pyruvate levels prevents hypertrophy.

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  • Bertero, E. & Maack, C. Metabolic remodelling in heart failure. Nat. Rev. Cardiol. 15, 457–470 (2018)

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  1. Nature Reviews Cardiology http://www.nature.com/nrcardio/

    Irene Fernández-Ruiz

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  1. Irene Fernández-Ruiz
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Correspondence to Irene Fernández-Ruiz.

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Fernández-Ruiz, I. Rebalancing the pyruvate–lactate axis to treat heart failure. Nat Rev Cardiol 18, 150–151 (2021). https://doi.org/10.1038/s41569-021-00513-8

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  • DOI: https://doi.org/10.1038/s41569-021-00513-8

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