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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 295; no. 2; pp. E420 - E427
• Main Authors: Hyyti, Outi M, Olson, Aaron K, Ge, Ming, Ning, Xue-Han, Buroker, Norman E, Chung, Youngran, Jue, Thomas, Portman, Michael A
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2008
• Subjects: Acetoacetates - metabolism; Acetyl Coenzyme A - metabolism; Animals; Citric Acid Cycle; Fatty acids; Fatty Acids, Nonesterified - metabolism; Glucose Transporter Type 4 - metabolism; Heart; Hexokinase - metabolism; Hormones; Immunoblotting; In Vitro Techniques; Lactic Acid - metabolism; Magnetic Resonance Spectroscopy; Male; Metabolism; Mice; Mice, Transgenic; Mutation; Myocardial Contraction - physiology; Myocardium - metabolism; Oxygen Consumption - physiology; Succinate Dehydrogenase - metabolism; Thyroid gland; Thyroid Hormone Receptors beta - metabolism
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90329.2008

1 Division of Cardiology, Department of Pediatrics and 2 Department of Radiology, University of Washington; 3 Children's Hospital and Regional Medical Center, Seattle, Washington; and 4 Department 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 TRβ 1 mutation 337T. Isolated working 337T hearts and nontransgenic control (Con) hearts were perfused with 13 C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13 C 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 (M O 2 ). 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 M O 2 . 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 Address for reprint requests and other correspondence: M. A. Portman, Children's Hospital and Regional Medical Center MSW 4841, 4800 Sand Point Way NE, Seattle, WA, 98105 (e-mail: michael.portman{at}seattlechildrens.org )