Michael G. Atser, Sareh Panahi, Justin J. Hong, Xiaoke Hu, Aura Balita, Haoning Howard Cen, Sing-Young Chen, Vincent R. Richard, Timon Geib, Armando Alcazar Magana, Brian Rodrigues, Leonard J. Foster, Elizabeth J. Rideout, Christoph H. Borchers, James D. Johnson
Abstract Pyruvate dehydrogenase kinase 1 (PDK1) inhibits pyruvate dehydrogenase (PDH) and therefore may regulate the balance between glucose and fatty acid oxidation in cardiomyocytes. We assessed metabolism and function in tamoxifen-inducible, cardiomyocyte-specific Pdk1 knockout ( Pdk1cKO ) mice, including both males and females fed a high fat diet, to resolve the role of PDK1 in the heart. Female, but not male, Pdk1cKO hearts showed the expected increase in cardiac PDH activity. Though cardiac function was largely preserved, female Pdk1cKO hearts had smaller left ventricles. Proteomics and phosphoproteomics revealed no change in classical hypertrophic markers but downregulated aerobic respiration alongside upregulated Ca 2+ handling and Rho signalling, suggesting metabolic remodeling with altered cardiomyocyte contractility and cytoarchitecture in Pdk1cKO hearts. Concordantly, lipidomics revealed membrane remodeling marked by elevated saturated phosphatidylcholine in female Pdk1cKO hearts and decreased triacylglycerols, free fatty acids and fatty acid uptake proteins (CD36, FABP3). These findings reveal novel, female-predominant cardiometabolic roles for PDK1.