Cardioselective dominant-negative thyroid hormone receptor (Δ337T) modulates myocardial metabolism and contractile efficiency

Dominantnegative 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 TR beta(1) mutation Delta 337T. Isolated working Delta 337T hearts and nontransgenic control (Con) hearts were perfused with C-13-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. C-13 NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Delta 337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MVO2). Unlabeled substrate Fc from endogenous sources was higher in Delta 337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Delta 337T. CE and Fc differences were reversed by pacing Delta 337T to Con rates, accompanied by an increase in FFA Fc. Delta 337T hearts lacked the ability to increase MVO2. 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 Delta 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.