Exercise Metabolic Memory Halts Pathological Cardiac Hypertrophy via PDK4

BACKGROUND: Pathological cardiac hypertrophy remains a major contributor to heart failure, with impaired glucose metabolism playing a central role. Although exercise is known to enhance myocardial glucose utilization, the long-term metabolic reprogramming effects of exercise and their role in preventing pathological hypertrophy are poorly understood. This study elucidates the mechanisms underlying the sustained metabolic memory induced by exercise-induced hypertrophic preconditioning (EHP) and its cardioprotective effects, with a focus on RNA methylation and arachidonic acid metabolism. METHODS: by EHP was investigated using pyrosequencing, single-base elongation- and ligation-based quantitative polymerase chain reaction and dual-luciferase assays. Untargeted metabolomics and molecular docking, molecular dynamics simulation, and cellular thermal shift assay were performed on heart tissues and neonatal rat cardiomyocytes/fibroblasts to identify key metabolites and their mechanisms of action. RESULTS: deletion enhanced cardiac function and attenuated fibrosis under pressure overload. Metabolomic profiling identified arachidonic acid-derived metabolites 5-KETE, 12-keto-leukotriene B4, and 20-hydroxy-leukotriene B4 as novel inhibitors of hypertrophy and fibrosis. These metabolites attenuated cardiomyocyte hypertrophy and fibroblast transdifferentiation through inhibition of the ERK (extracellular signal-regulated kinase) 2/MAPK1 pathway. CONCLUSIONS: , leading to altered arachidonic acid metabolism and the accumulation of protective lipid mediators. These findings highlight the therapeutic potential of targeting the PDK4-arachidonic acid metabolites axis to mitigate pathological cardiac remodeling.