Chengyi Tu, Arianne Caudal, Yu Liu, Nikoloz Gorgodze, Hao Zhang, Chi Keung Lam, Yuqin Dai, Angela Zhang, Alexa Wnorowski, Matthew A Wu, Huaxiao Yang, Oscar J Abilez, Xuchao Lyu, Sanjiv M Narayan, Luisa Mestroni, Matthew R G Taylor, Fabio A Recchia, Joseph C Wu
Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase), a molecular signature of heart failure...
November 27, 2023: Nature Biomedical Engineering