title: Calcineurin-induced energy wasting in a transgenic mouse model of heart failure.
abstract: Overexpression of calcineurin (CLN) in the mouse heart induces severe hypertrophy that progresses to heart failure, providing an opportunity to define the relationship between energetics and contractile performance in the severely failing mouse heart. Contractile performance was studied in isolated hearts at different pacing frequencies and during dobutamine challenge. Energetics were assessed by 31P-NMR spectroscopy as ATP and phosphocreatine concentrations ([ATP] and [PCr]) and free energy of ATP hydrolysis (|Delta G( approximately ATP)|). Mitochondrial and glycolytic enzyme activities, myocardial O2 consumption, and myocyte ultrastructure were determined. In transgenic (TG) hearts at all levels of work, indexes of systolic performance were reduced and [ATP] and capacity for ATP synthesis were lower than in non-TG hearts. This is the first report showing that myocardial [ATP] is lower in a TG mouse model of heart failure. [PCr] was also lower, despite an unexpected increase in the total creatine pool. Because Pi concentration remained low, despite lower [ATP] and [PCr], |Delta G( approximately ATP)| was normal; however, chemical energy did not translate to systolic performance. This was most apparent with beta-adrenergic stimulation of TG hearts, during which, for similar changes in |Delta G( approximately ATP)|, systolic pressure decreased, rather than increased. Structural abnormalities observed for sarcomeres and mitochondria likely contribute to decreased contractile performance. On the basis of the increases in enzyme activities of proteins important for ATP supply observed after treatment with the CLN inhibitor cyclosporin A, we also conclude that CLN directed inhibition of ATP-producing pathways in non-TG and TG hearts.
authors.affiliation: NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ilka
authors.initials: I
authors.lastname: Pinz
authors.forename: Sanford E
authors.initials: SE
authors.lastname: Ostroy
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoyer
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Ingwall
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000494:pharmacology*; D003401:Creatine / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism
chemical_list: D010725:Phosphocreatine; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D019703:Calcineurin; D003401:Creatine