Dominant- negative thyroid hormone receptors (TRs) show elevated expression
relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRß1 mutation ?337T. Isolated working ?337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA),
acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). ?337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV? O2). Unlabeled substrate Fc from
endogenous sources was higher in ?337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in ?337T. CE and Fc differences were reversed by pacing ?337T to Con rates, accompanied by an increase in FFA Fc. ?337T hearts lacked the ability to increase MV? O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase
kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that ?337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be
disrupted by pacing stress.
Revised: January 7, 2011 |
Published: June 3, 2008