Abstract 13620: Loss of Pkm2 Alters Myocardial Glucose Levels Before and After Infarction

IntroductionPyruvate kinase is a key enzyme in glucose metabolism, converting phosphoenolpyruvate to pyruvate. The muscle-specific isoform (Pkm1) is highly expressed in the heart and directs pyruvate to the TCA cycle. In contrast, its alternatively spliced isoform (Pkm2) favors the conversion of pyruvate to lactate and is largely absent in the healthy heart. Our lab recently described a hypoxia-mediated switch in Pkm isoform expression after myocardial infarction (MI), with a rapid loss of Pkm1 expression and a concomitant increase in Pkm2 expression. We hypothesize that this increase in Pkm2 alters metabolism after injury to favor glycolysis, and preserve ATP production in hypoxia.MethodsGlobal Pkm2 knockout (KO) mice were generated and subjected to permanent ligation of the left anterior descending coronary artery to mimic an MI. Heart function was assessed by echocardiography 3 days after injury and metabolite changes in cardiac tissue and plasma were quantified by mass spectrometry.ResultsWhile loss of Pkm2 did not affect fractional shortening at baseline or after MI, an increased heart weight to body weight ratio after injury was substantially reduced in Pkm2 KO mice (6.0 mg/g ± 0.4, n=10) compared to controls (6.5 mg/g ± 0.7, n=13). Metabolic analysis revealed a significant reduction in tissue glucose (48 vs. 17 ng/mg, p=0.05) and fructose (3.8 vs. 1.5 ng/mg, p=0.03) in Pkm2 KO mice (n=4) compared to controls at baseline (n=3). In contrast, glucose levels in the ischemic myocardium were higher in both control and Pkm2 KO mice after MI (102 and 93 ng/mg, respectively, n=4 per group, p