title: Narrow time window of metabolic changes associated with transition to overt heart failure in Tgaq*44 mice.
abstract: 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 Gαq*.
  
  
  METHODS
  Structural changes quantified by morphometry, relative cardiac mRNA and protein expression of PPARα, FAT/CD36, CPT-1, GLUT-4 and glycolytic efficiency following administration of 1-(13)C glucose were investigated in 4-14-month-old Tgαq*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 PPARα. During the transition phase (12-month-old TG), a pronounced increase in PPARα 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.
  
  
  CONCLUSIONS
  Tgαq*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 Tgaq*44 mice that have therapeutic significance.
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warszawa, Poland. Electronic address: e.czarnowska@czd.pl.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Czarnowska
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warszawa, Poland.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Bierła
authors.affiliation: Department of Biochemistry, Medical University of Gdansk, Gdańsk, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Toczek
authors.affiliation: Department of Magnetic Resonance Imaging Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland; Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Tyrankiewicz
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland; Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences - SGGW, Warszawa, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Pająk
authors.affiliation: Department of Biochemistry, Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Sosnowiec, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Domal-Kwiatkowska
authors.affiliation: Department of Pathology, The Medical University of Warsaw, Warszawa, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ratajska
authors.affiliation: Department of Biochemistry, Medical University of Gdansk, Gdańsk, Poland.
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smoleński
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Department of Experimental Pharmacology, Jagiellonian University Medical College, Kraków, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chłopicki
mesh_terms: D000367:Age Factors; D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D016923:Cell Death; D005227:Fatty Acids / Q000096:biosynthesis; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000096:biosynthesis
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D047493:PPAR alpha; C495693:Slc2a4 protein, mouse; D002334:Carnitine O-Palmitoyltransferase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: Heart failure; Hypertrophy; Metabolic remodeling; PPARα; Structural remodeling