Progressive loss of creatine maintains a near normal DeltaG approximately (ATP) in transgenic mouse hearts with cardiomyopathy caused by overexpressing Gsalpha

Abstract

Myocardial [ATP] falls in the failing heart. One potential compensatory mechanism for maintaining a near normal free energy of ATP hydrolysis (DeltaG approximately (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 Gsalpha, which slowly developed cardiomyopathy. Myocardial energetics measured using (31)P NMR spectroscopy and isovolumic contractile performance were determined in perfused hearts isolated from 5-, 10-, 17-month-old Gsalpha and age-matched littermate wild type (WT) mice. In young Gsalpha hearts, contractile performance was enhanced with near normal cardiac energetics. With age, as contractile performance progressively decreased in Gsalpha hearts, [ATP] and [PCr] progressively decreased while [Pi] increased only modestly; no changes were observed in WT hearts. Myocardial (but not skeletal) [Cr] in Gsalpha 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 Gsalpha hearts, despite decreased [ATP]. During increased cardiac work caused by supplying isoproterenol, the relationship between the rate pressure product (RPP) and DeltaG approximately (ATP) in Gsalpha 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.