Abstract

While timely reperfusion is essential to rescue ischemic myocardium, it paradoxically induces additional reperfusion injury. Energy metabolic reprogramming is implicated in this process, yet its precise mechanisms remain poorly understood. This study aims to compare the energy metabolic profiles during myocardial ischemia versus reperfusion phases, and to evaluate whether stage-specific inhibition of glycolysis could differentially mitigate injury. In a mouse model, glycolysis was enhanced during myocardial ischemia, accompanied by suppressed glucose and fatty acid oxidation. In contrast, both glycolysis and fatty acid oxidation were upregulated while glucose oxidation remained suppressed in mice hearts subjected to myocardial ischemia/reperfusion. Inhibiting glycolysis at its initial step (glucose phosphorylation) using a hexokinase inhibitor alleviated reperfusion injury but exacerbated ischemic injury. However, inhibition at the pyruvate-to-lactate conversion stage via a lactate dehydrogenase inhibitor alleviated reperfusion injury without aggravating ischemic injury. Similar results were observed in cultured cardiomyocytes exposed to either hypoxia alone or hypoxia/reoxygenation. Based on these observations, we conclude that adaptive glycolysis upregulation during ischemia contributes to energy metabolic reprogramming in reperfusion. Precise intervention at the pyruvate-to-lactate conversion stage restores glycolytic-glucose oxidation coupling in the heart, thereby mitigating reperfusion injury without aggravating ischemic damage.