title: Metabolic efficiency promotes protection from pressure overload in hearts expressing slow skeletal troponin I.
abstract: BACKGROUND
  The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In this study, we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload.
  
  
  RESULTS
  At 2 to 3 months of age, ssTnI mice or their nontransgenic littermates underwent aortic constriction (TAC). TAC induced a 25% increase in nontransgenic heart size but only a 7% increase in ssTnI hearts (P<0.05). Nontransgenic TAC developed diastolic dysfunction (65% increase in E/A ratio), whereas the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from nontransgenic TAC mice showed reduced cardiac function and reduced creatine phosphate:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting nontransgenic TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in nontransgenic TAC hearts. Elevated glucose oxidation was mediated by a reduction in pyruvate dehydrogenase kinase 4 expression, enabling pyruvate dehydrogenase to compete against anaplerotic enzymes for pyruvate carboxylation.
  
  
  CONCLUSIONS
  Expression of a single fetal myofilament protein into adulthood in the ssTnI-transgenic mouse heart induced downregulation of the gene expression response for pyruvate dehydrogenase kinase to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.
authors.affiliation: From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Carley
authors.affiliation: From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine.
authors.forename: Domenico M
authors.initials: DM
authors.lastname: Taglieri
authors.affiliation: From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine.
authors.forename: Jian
authors.initials: J
authors.lastname: Bi
authors.affiliation: From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine. dougl@uic.edu.
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019210:Troponin I / Q000096:biosynthesis*
chemical_list: D019210:Troponin I; D005947:Glucose
keywords: contractile proteins; energy metabolism; enzymes; hypertrophy