title: Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice.
abstract: BACKGROUND
  Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT).
  
  
  RESULTS
  We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66+/-6 nmol/mg protein in WT versus 133+/-52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5+/-4.3 microL in WT versus 33.1+/-9.6 microL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64+/-9% in WT versus 49+/-13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dt(max) (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels.
  
  
  CONCLUSIONS
  Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford, England.
authors.forename: Julie
authors.initials: J
authors.lastname: Wallis
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fischer
authors.forename: Michiel
authors.initials: M
authors.lastname: ten Hove
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Schneider
authors.forename: Liam
authors.initials: L
authors.lastname: Sebag-Montefiore
authors.forename: Dana
authors.initials: D
authors.lastname: Dawson
authors.forename: Karen
authors.initials: K
authors.lastname: Hulbert
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Zhang
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000503:physiopathology*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016366:Open Reading Frames; D011817:Rabbits; D012508:Sarcolemma / Q000502:physiology
chemical_list: D026901:Membrane Transport Proteins; C080679:creatine transporter