title: Mouse strain differences in metabolic fluxes and function of ex vivo working hearts.
abstract: In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism-a factor known to be closely related to function and contributes to disease development-is, however, unclear. This was examined in this study. In commonly used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J, and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3-mo-old working mouse hearts perfused ex vivo with physiological concentrations of (13)C-labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7-fold vs. SJL/JCrNTac and C57Bl/6J; P < 0.05), whereas at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (~-3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between 1) glycolysis, FA oxidation, and pyruvate metabolism and 2) cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.
authors.affiliation: Departments of Nutrition, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; and.
authors.forename: Fanny
authors.initials: F
authors.lastname: Vaillant
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lauzier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Poirier
authors.forename: Roselle
authors.initials: R
authors.lastname: Gélinas
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Rivard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Robillard Frayne
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000235:genetics*; D050260:Carbohydrate Metabolism; D002302:Cardiac Output / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis; D006321:Heart / Q000502:physiology*; D015227:Lipid Peroxidation; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption; D019289:Pyruvic Acid / Q000378:metabolism; D013045:Species Specificity; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; D019289:Pyruvic Acid
keywords: function; genetic background; isolated working heart; metabolism