Narrow time window of metabolic changes associated with transition to overt heart failure in Tgaq*44 mice

Background: The timing and consequences of alternations in substrate utilization in heart failure (HF) and their relationship with structural changes remain unclear. This study aimed to analyze metabolic changes associated with transition to overt heart failure in transgenic mouse model of HF resulting from cardiac-specific overexpression of constitutively active G alpha(q)*. Methods: Structural changes quantified by morphometry, relative cardiac mRNA and protein expression of PPAR alpha, FAT/CD36, CPT-1, GLUT-4 and glycolytic efficiency following administration of 1-C-13 glucose were investigated in 4-14-month-old Tg alpha(q)*44 mice (TG), compared with age-matched FVB wild type mice (WT). Results: Initial hypertrophy in TG (4-10-month of age) was featured by an accelerated glycolytic pathway that was not accompanied by structural changes in cardiomyocytes. In 10-month-old TG, cardiomyocyte elongation and hypertrophic remodeling and increased glycolytic flux was accompanied by relatively low expression of FAT/CD36, CPT-1 and PPAR alpha. During the transition phase (12-month-old TG), a pronounced increase in PPAR alpha with an increase in relative fatty acid (FA) flux was associated with anomalies of cardiomyocytes with accumulation of lipid droplets and glycogen as well as cell death. At the stage of overt heart failure (14-month-old TG), an accelerated glycolytic pathway with a decline in FA oxidation was accompanied by further structural changes. Conclusion: Tg alpha(q)*44 mice display three distinct phases of metabolic/structural changes during hypertrophy and progression to HF, with relatively short period of increase in FA metabolism, highlighting a narrow metabolic changes associated with transition to overt heart failure in Tg alpha(q)*44 mice that have therapeutic significance. (C) 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.