Abstract 4146509: L-Lactic Acid Reduces Infarct Size After Ischemia In Isolated Mouse Hearts Through Acidosis, MCT1-Mediated Uptake, And Metabolic Reprogramming

Introduction: Lactic acid is increasingly recognized as an alternative fuel source for various tissues, including the brain and heart. It is acknowledged as a protective compound in tissues such as the brain, particularly under conditions like traumatic brain injury or ischemia-reperfusion. However, its potential as a cardioprotective agent remains controversial. Aims: We aimed to (1) evaluate the impact of acute L-lactic acid administration at reperfusion onset on myocardial infarct size in isolated mouse hearts after transient global ischemia, and (2) elucidate the underlying mechanisms. Methods: Isolated mouse hearts underwent 35 min global ischaemia followed by 60 min of reperfusion and were randomly assigned to experimental groups. Control hearts (n=7) received standard Krebs buffer, while L-lactic acid-treated hearts received Krebs containing 8 or 20 mmol/L L-lactic acid for the first 15 minutes of reperfusion (n=5). To assess the contribution of acidosis to the observed effects, 5 hearts were treated with acidic Krebs (pH 7.0) for the same time period. To evaluate the role of import of L-lactic acid through monocarboxylate transporter 1 (MCT1) in those effects, additional hearts (n=6) were treated with L-lactic acid and 1 μmol/L AR-C141990 hydrochloride. Results: L-lactic acid induced a concentration-dependent reduction in infarct size, achieving a 23% reduction at 20 mmol/L (from 44.74±2.24 to 21.46±1.93%, ANOVA and Tukey’s tests, p=0.0006). This protective effect was associated with reduced lactate dehydrogenase release and improved functional recovery during reperfusion. Perfusion with an acidic Krebs also reduced infarct size, but to a lesser extent than L-lactic acid (see Figure). MCT1 inhibition with AR-C 141990 attenuated the protective effect of L-lactic acid to the levels seen with the acidic Krebs (see Figure). 1 H NMR spectroscopy revealed significant metabolic changes in L-lactic acid-treated hearts, with pathway enrichment analysis indicating nearly a 3-fold enrichment in pyruvate metabolism, fatty acid biosynthesis, and gluconeogenesis, suggestive of a metabolic shift. Conclusions: These findings support a cardioprotective role for L-lactic acid against ischemia-reperfusion injury, attributable to both acidosis and MCT1-mediated uptake, leading to metabolic reprogramming.