Original Research
2020 Dec 11;S1550-4131(20)30658-6.
JOURNAL：Cell Metab.
Article Link
The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure
AA Cluntun, R Badolia, SG Drakos et al.
KEYWORDS
LVAD; MCT4; MPC; VB124; cardiac metabolism; heart failure; hypertrophy; lactate; mitochondria; pyruvate
The metabolic rewiring of cardiomyocytes is a widely accepted hallmark
of heart failure (HF). These metabolic changes include a decrease in
mitochondrial pyruvate oxidation and an increased export of lactate. We
identify the mitochondrial pyruvate carrier (MPC) and the cellular
lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes
in this metabolic axis. We observed that cardiac assist device-induced
myocardial recovery in chronic HF patients was coincident with increased
myocardial expression of the MPC. Moreover, the genetic ablation of the
MPC in cultured cardiomyocytes and in adult murine hearts was
sufficient to induce hypertrophy and HF. Conversely, MPC overexpression
attenuated drug-induced hypertrophy in a cell-autonomous manner. We also
introduced a novel, highly potent MCT4 inhibitor that mitigated
hypertrophy in cultured cardiomyocytes and in mice. Together, we find
that alteration of the pyruvate-lactate axis is a fundamental and early
feature of cardiac hypertrophy and failure.
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