Sphingosine-1-Phosphate Lyase Inhibition Increases Glycolysis in Adult Cardiomyocytes and Restores Glycolytic Flux in Diabetic Cardiomyopathy.

Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects cardiac contractility and calcium homeostasis and exerts potent cardioprotective properties in myocardial infarction, heart failure, preconditioning. Whether and how it may affect energy metabolism in the heart is still unknown. Here, we examined S1P effects on glycolysis of adult cardiomyocytes (ACM) using Seahorse technology and observed that intracellular S1P rather than extracellular S1P potently potentiates basal glycolysis and increases glycolytic capacity. Accordingly, ACM from mice administered a S1P lyase inhibitor to prevent S1P degradation featured 3-fold higher S1P levels and a 30%-40% increase in basal glycolysis and glycolytic capacity, whereas acute S1P stimulation had no effect. Cardiomyocyte-specific GLUT4-deficient ACM were resistant to this increase, whereas ACM from S1P lyase-inhibited mice featured a 3-fold higher glucose uptake, suggesting that higher glycolysis may be a function of increased glucose influx through GLUT4. Comparing glycolysis in ACM from normal chow-fed mice with ACM from pre-diabetic mice following long-term feeding of a high caloric diet revealed a rapid and progressive loss of glycolytic potential without yet affecting cardiac function despite a beginning hypertrophy on echocardiography. Most importantly, both could be reconstituted to normal by S1P lyase inhibition. As the levels of bioactive lipids such as S1P are altered in obesity and diabetes, understanding their effects on metabolism may help reveal novel aspects of lipid biology in metabolic diseases of the heart.