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.

心肌细胞的代谢重新布线是心力衰竭 (HF) 的一个广泛接受的标志。这些代谢变化包括线粒体丙酮酸氧化减少和乳酸输出增加。我们将线粒体丙酮酸载体 (MPC) 和细胞乳酸输出蛋白单羧酸转运蛋白 4 (MCT4) 确定为该代谢轴的关键节点。我们观察到心脏辅助装置诱导的慢性 HF 患者心肌恢复与 MPC 心肌表达增加一致。此外，在培养的心肌细胞和成年鼠心脏中 MPC 的基因消融足以诱导肥大和 HF。相反，MPC 过表达以细胞自主方式减弱药物诱导的肥大。我们还介绍了一部小说，高效的 MCT4 抑制剂，可减轻培养的心肌细胞和小鼠的肥大。总之，我们发现丙酮酸-乳酸轴的改变是心脏肥大和衰竭的基本和早期特征。