Exercise enhances cardiac Pect expression to restore phosphatidylethanolamine synthesis and alleviate high-sugar...

High dietary sugar intake is recognized as an important risk factor for cardiovascular disease, yet the precise mechanisms that drive these pathologies remain incompletely understood. To delineate the molecular impact of hyperglycemia on the myocardium, we analyzed RNA-sequencing data from hiPSC-derived cardiomyocytes of a diabetic model (GSE288708). The analysis revealed a marked downregulation of Pcyt2 mRNA in cardiomyocytes exposed to a hyperglycemic environment. In vivo validation in Drosophila showed that a high-sugar diet (HSD) suppresses expression of Pect-the Drosophila homolog of human Pcyt2-in the heart, and that Pect knockdown reproduces HSD-induced metabolic disturbances and cardiac dysfunction. An exercise regimen partially rescued the cardiac phenotype: exercise restored cardiac Pect expression and phosphatidylethanolamine (PE) content, preserved mitochondrial integrity and redox homeostasis, and ameliorated cardiac fibrosis and functional decline. Notably, cardiac-specific knockdown of Pect impeded the ability of exercise to confer these partial improvements, implicating the Pect/PE biosynthetic pathway as a potential therapeutic target for HSD-induced cardiomyopathy. These findings establish a previously underappreciated pathway through which diet and exercise jointly regulate heart health via Pect-PE modulation.