Abstract 4362835: Divergent Roles of PDK2 and PDK4 in Regulating Survival, Hypertrophy, and Metabolism Under Physiological and Pathological Cardiac Stress

Cardiac hypertrophy can be induced by both physiological (e.g., exercise) and pathological (e.g., pressure overload) stress. These adaptive responses are accompanied by distinct shifts in myocardial energy metabolism. Pathological hypertrophy typically increases glucose utilization, while physiological stress promotes fatty acid oxidation. The pyruvate dehydrogenase complex (PDC), a critical regulator of glucose oxidation, is inactivated via phosphorylation by pyruvate dehydrogenase kinases (PDKs), in the heart by PDK2 and PDK4. Loss of PDK4 can protect cardiac metabolism during ischemic injury, however the role of PDK2 remains poorly defined and neither have been extensively studied in other contexts. We hypothesized that loss of PDK2 or PDK4 alters the cardiac response to these stressors. We utilized germline knockout mice ( P2 -/- and P4 -/- ; C57BL/6J) subjected to transverse aortic constriction (TAC; n>15) or swim training (n>8). 8-wks post-TAC, WT survival was similar in males 79% and females 79% (p<0.05 vs. Sham). P2 -/- mice had enhanced survival (M: 93%, F: 97%), while P4 -/- M had reduced survival (57%, p<0.05 vs WT-TAC), with F had no significant change (81%). Cardiac hypertrophy mirrored survival outcomes. Compared to genotype-matched Sham, LV hypertrophy increased in WT-TAC (M: 152%, F: 158%, p<0.001 vs Sham), P2 -/- (M: 137%, F: 145%), and was exaggerated in P4 -/- (M: 177%, F: 168%, p<0.05 vs WT-TAC). In the swim model, M P2 -/- mice had mortality (43%; p<0.05) compared to WT (6%) and P4 -/- (5%), while F mortality was comparable across groups. Despite differences in survival, LV hypertrophy in P2 -/- -Swim (M: 114%, F:126%) was not significantly different from WT-Swim (M: 119%, F: 122%). P4 -/- -Swim mice showed similar hypertrophy (M: 113%, F: 124%), with all Swim groups exhibiting significant hypertrophy (p<0.01). Targeted metabolomics of cardiac tissue revealed distinct metabolic signatures. P2 -/- hearts showed altered glycolytic metabolites, while P4 - - hearts exhibited shifts in fatty acid oxidation intermediates. In addition to the metabolites, P4 -/- showed down regulation of fatty acid oxidation related genes including Cd36 , Cpt1b , and Mcad . In conclusion, PDK2 and PDK4 deletions yield divergent effects on cardiac survival, hypertrophy, and metabolic adaptation under physiological and pathological stress. These findings underscore the distinct roles of PDK isoforms in regulating cardiac metabolic flexibility in response to hemodynamic demand.