Abstract 19448: Altered Cardiomyocyte Glycolysis Causes Cardiac Hypertrophy and Mitochondrial Dysfunction
Introduction: The failing heart is characterized by high rates of glycolysis and low rates of fatty acid oxidation, whereas the diabetic heart shows an opposite cardiac metabotype; however, the role of metabolic changes on myocardial health and mitochondrial function is unclear.
Hypothesis: We tested whether metabolic changes that partially phenocopy those occurring in the failing and diabetic heart are sufficient to cause mitochondrial dysfunction and cardiac hypertrophy.
Methods/Results: We determined how polarizing cardiac metabolism towards glucose or fat utilization affects cardiac phenotype. Mice expressing cardiac-specific dominant-negative (GlycoLO) phosphofructokinase 2, which decreases glycolytic rate, showed remarkably lower levels of acylcarnitines and fatty acids; conversely, GlycoHI hearts having high glycolytic rates demonstrated increased levels of numerous acylcarnitine species and higher levels of phospholipids compared with WT littermates (A). Both transgenic models displayed hypertrophic hearts (B,C). The lipid peroxidation product 4-HNE was higher in both groups (p<0.05). Electron micrographs of both transgenic hearts showed decreased mitochondrial cristae density and organization. Mitochondria isolated from GlycoLO and GlycoHI hearts showed lower state 3 respiration (D) and diminished respiratory control ratios (p<0.05). Cardiomyocytes transduced with GlycoHI and GlycoLO viruses subjected to extracellular flux analysis and 13C6-glucose stable isotope metabolomics showed that mitochondrial activity and ancillary biosynthetic pathway flux are dependent on glycolytic rate (p<0.05, n = 3/group).
Conclusions: Imbalanced glucose metabolism recapitulates several facets of the diseased myocardium, including mitochondrial dysfunction and myocardial hypertrophy. These findings support the concept the metabolic inflexibility is a causative factor in cardiac dysfunction in diabetes and heart failure.
- Cardiac metabolism
- Cardiac hypertrophy
- Mitochondrial energetics, heart failure, arrhythmias
Author Disclosures: A.A. Gibb: None. L.A. Gilbert: None. P. Lorkiewicz: None. P. Trainor: None. M.T. Tseng: None. P.N. Epstein: None. A. Bhatnagar: None. B.G. Hill: None.
- © 2016 by American Heart Association, Inc.