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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/E420    most recent 90329.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hyyti, O. M. Articles by Portman, M. A. PubMed PubMed Citation Articles by Hyyti, O. M. Articles by Portman, M. A.

Cardioselective dominant-negative thyroid hormone receptor (337T) modulates myocardial metabolism and contractile efficiency

¹Division of Cardiology, Department of Pediatrics and ²Department of Radiology, University of Washington; ³Children's Hospital and Regional Medical Center, Seattle, Washington; and ⁴Department of Biological Chemistry, University of California, Davis, California

Submitted 2 April 2008 ; accepted in final form 27 May 2008

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 TRβ₁ 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 (MO₂). 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 MO₂. 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.

glucose metabolism; free fatty acids