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Thyroid hormone controls myocardial substrate metabolism through nuclear receptor-mediated and rapid posttranscriptional mechanisms

¹Division of Cardiology, Department of Pediatrics, and ²Department of Radiology, University of Washington, and ³Children's Hospital and Regional Medical Center, Seattle Washington

Submitted 24 June 2005 ; accepted in final form 27 September 2005

Thyroid hormone regulates metabolism through transcriptional and posttranscriptional mechanisms. The integration of these mechanisms in heart is poorly understood. Therefore, we investigated control of substrate flux into the citric acid cycle (CAC) by thyroid hormone using retrogradely perfused isolated hearts (n = 20) from control (C) and age-matched thyroidectomized rats (T). We determined substrate flux and fractional contributions (Fc) to the CAC by ¹³C-NMR spectroscopy and isotopomer analyses in hearts perfused with [1,3-¹³C]acetoacetic acid (0.17 mM), L-[3-¹³C]lactic acid (LAC, 1.2 mM), [U-¹³C]long-chain mixed free fatty acids (FFA, 0.35 mM), and unlabeled glucose. Some T hearts were supplied triiodothyronine (T₃, 10 nM; TT) for 60 min. Prolonged hypothyroid state reduced myocardial oxygen consumption, although T₃ produced no significant change. Hypothyroidism reduced overall CAC_flux but selectively altered only FFA_flux among the individual substrates, though LAC_flux trended upward. T₃ rapidly decreased lactate Fc and flux. ¹³C labeling of glutamine through glutamate was increased in T with further enhancement in TT. The glutamate-to-glutamine ratio was significantly lower in T and TT. Immunoblots detected a decrease in hypothyroid hearts for muscle carnitine palmitoyltransferase I (CPT I) and a marked increase in pyruvate dehydrogenase kinase (PDK)-2 with no changes in liver CPT I, PDK-4, or hexokinase 2. TT, but not T, displayed elevated glutamine synthetase (GS) expression. These studies showed that T₃ regulates cardiac metabolism through integration of several mechanisms, including changes in oxidative enzyme content and rapid modulation of individual substrates fluxes. T₃ also moderates forward glutamine flux, possibly by increasing the overall activity of GS.

citric acid cycle; carnitine palmitoyltransferase I; pyruvate dehydrogenase kinase

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