Progressive loss of creatine maintains a near normal ΔG∼ATP in transgenic mouse hearts with cardiomyopathy caused by overexpressing Gsα

Weiqun Shen, Dorothy E. Vatner, Stephen F. Vatner, Joanne S. Ingwall

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13 Scopus citations

Abstract

Myocardial [ATP] falls in the failing heart. One potential compensatory mechanism for maintaining a near normal free energy of ATP hydrolysis (ΔG∼ATP), despite a fall in [ATP], may be the reduction of myocardial creatine (Cr). To test this, we conducted a longitudinal study using transgenic mice overexpressing cardiac Gsα, which slowly developed cardiomyopathy. Myocardial energetics measured using 31P NMR spectroscopy and isovolumic contractile performance were determined in perfused hearts isolated from 5-, 10-, 17-month-old Gsα and age-matched littermate wild type (WT) mice. In young Gsα hearts, contractile performance was enhanced with near normal cardiac energetics. With age, as contractile performance progressively decreased in Gsα hearts, [ATP] and [PCr] progressively decreased while [Pi] increased only modestly; no changes were observed in WT hearts. Myocardial (but not skeletal) [Cr] in Gsα mice decreased, beginning at an early age (1.5 months). Consequently, cytosolic [ADP] and the free energy available from ATP hydrolysis were maintained at normal levels in Gsα hearts, despite decreased [ATP]. During increased cardiac work caused by supplying isoproterenol, the relationship between the rate pressure product (RPP) and ΔG∼ATP in Gsα mouse hearts demonstrated an increased cost of contraction in failing hearts. Thus, our results suggest that the decrease of myocardial [Cr] and net Pi efflux play compensatory roles by maintaining a nearly normal free energy of ATP hydrolysis in the dysfunctional heart; however, it also increased the cost of contraction, which may contribute to the lower contractile reserve in the failing heart.

Original languageEnglish (US)
Pages (from-to)591-599
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number4
DOIs
StatePublished - Apr 2010

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Molecular Biology

Keywords

  • Adenosine triphosphate
  • Cardiomyopathy
  • Creatine
  • Gsα transgenic mice
  • ΔG∼

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