PKM2 is a key regulator of cardiac lipid metabolism in mice

Deficiencies in lipid metabolism can have severe consequences for cardiac function. We previously showed that regulating glucose flux by pyruvate kinase 2 (PKM2) affects lipid synthesis and droplet abundance in cardiomyocytes. This study aims to examine how PKM2 regulates lipid metabolism in the heart. Indirect calorimetry suggested similar whole-body metabolism of PKM2 knockout (PKM2^-/-) and control (PKM2^fl/fl) young mice (2-3 months), but indicated that lipids were utilized to a greater degree in aged (1-year) PKM2^-/- mice compared to controls. Metabolic chamber studies also revealed an overall negative energy balance that contributed to reduced exercise tolerance in aged PKM2^-/- mice. Metabolomics showed substantially lower carnitine levels in PKM2^-/- cardiomyocyte fractions (CM), alongside increased circulating and cardiac dicarboxylic acids, as well as reduced mitochondrial palmitate oxidation in PKM2^-/- CM. We also noted a sex-specific difference in which female PKM2^-/- mice exhibited greater high-fat diet (HFD)-induced hyperglycemia and weight gain compared to PKM2^fl/fl females, while male PKM2^-/- mice fed a HFD were comparatively leaner than their PKM2^fl/fl counterparts. PKM2^-/- mice have aberrations in lipid metabolism that worsen with age, shifting whole-body metabolism towards a preference for lipid utilization. This may lead to a decline in aerobic capacity during exercise in aged PKM2^-/- mice. PKM2^-/- CM also display compromised mitochondrial lipid metabolism due to carnitine deficiency. Challenging PKM2^-/- mice with a HFD revealed sex-dependent differences in glycemic control and body weight. Our results indicate a role for PKM2 in sustaining the homeostasis of cardiac and whole-body lipid metabolism that contributes to overall physiological fitness.