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

Hyyti, Outi M.; Xue, Ning; Buroker, Norman E.; Ge, Ming; Portman, Michael A.

doi:10.1152/ajpendo.00288.2005

Cited by 36 publications

(34 citation statements)

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“…As noted previously, limited prior data exist regarding thyroid receptor modulation of myocardial metabolic phenotype. Studies in the hypothyroid rat heart demonstrate important transcriptionally mediated regulation of cardiac metabolism by thyroid hormone (14). Experiments in isolated perfused heart from euthyroid or hypothyroid rats indicate that triiodothyronine also exerts rapid modulation of cardiac substrate metabolism including enhancement of fatty acid flux (14,22).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in the hypothyroid rat heart demonstrate important transcriptionally mediated regulation of cardiac metabolism by thyroid hormone (14). Experiments in isolated perfused heart from euthyroid or hypothyroid rats indicate that triiodothyronine also exerts rapid modulation of cardiac substrate metabolism including enhancement of fatty acid flux (14,22). The rapidity of these latter actions implies that they do not occur through transcriptional processes controlled by thyroid receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Few prior studies have directly evaluated thyroid receptor control of these processes. Because the rates of activity for these ATPases determine contractile function and can influence energy expenditure in the intact heart, and ATP synthesis responds to energy demands, the hypothesis invoking thyroid receptor-mediated metabolic control of cardiac function remains difficult to evaluate.Although studies in hypothyroid or hyperthyroid models indicate that this hormone modulates cardiac energy metabolism (14,15,30), the inability to effectively dissect out thyroid receptor-mediated regulation of metabolism from posttranscriptional thyroid mechanisms has hampered study in this area. Esaki et al (5) attempted to evaluate thyroid receptor control of heart substrate metabolism by studying mice in vivo with non-organ-specific "knockin" (PV) mutations of the thyroid ␣-and ␤-receptors.…”

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confidence: 99%

“…More recently, several investigators alternatively postulated that thyroid modifies cardiac function through control of cardiac substrate metabolism and ATP synthesis (1,14,29). Few prior studies have directly evaluated thyroid receptor control of these processes.…”

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confidence: 99%

“…The substrate utilization profile was determined with 13 C substrate labeling and isotopomer analyses with protein analyses for key enzymes regulating the metabolic pathways in these isolated, perfused working hearts. The robust NMR method used in these studies allows analyses of fractional contribution (Fc) of acetyl-CoA to the citric acid cycle (CAC) from multiple substrates supplied to the heart simultaneously in physiological concentrations (14). These methods allowed analyses of the metabolic phenotype caused by a dominantnegative TR.…”

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

Hyyti

Olson

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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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 TRbeta(1) mutation Delta337T. Isolated working Delta337T 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). Delta337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MVo(2)). Unlabeled substrate Fc from endogenous sources was higher in Delta337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Delta337T. CE and Fc differences were reversed by pacing Delta337T to Con rates, accompanied by an increase in FFA Fc. Delta337T hearts lacked the ability to increase MVo(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 Delta337T 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Hyyti

Olson

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Perfused Cells, Tissues and Organs by Magnetic Resonance Spectroscopy

Milkevitch

Browning

Delikatny

2016

eMagRes

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In this article we review methods for the study of perfused cells, tissues, and organs using magnetic resonance spectroscopy (MRS). Biologically relevant nuclei and the different but often complementary information that they make available are presented. Pulse sequence implementation is discussed in the context of tailoring the desired metabolite information and suppressing unwanted resonances. Metabolites observable with MRS are generally limited to those present in relatively high (millimolar) concentrations. The importance of these metabolites and how flux through metabolic pathways can be observed using isotopic enhancement with 13 C is reviewed. Cell preparation and immobilization methods employing agarose threads, matrigel and alginate beads; and the use of porous and nonporous microcarriers, hollow fibers and bioreactors for perfused cell culture are discussed. Tissue preparation techniques for the study of perfused organs include the Langendorff heart, perfused liver, and lung preparations. Maintaining careful control of the perfusate composition, pH, oxygenation, and temperature all critically affect cell and organ viability as well as the measured levels of cell metabolites. The requisite apparatus for achieving this is reviewed. Perfusion model systems allow the acquisition of real-time kinetic metabolic information by MRS, providing unique insights into the effects of drugs and inhibitors on metabolite levels. They thus provide a valuable intermediate for translational research from cells to animals to humans and back again.

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Thyroid Hormone and Cardioprotection

Gerdes

Ojamaa

2016

Comprehensive Physiology

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The heart is a major target of thyroid hormones, with maintenance of euthyroid hormone balance critical for proper function. In particular, chronic low thyroid function can eventually lead to dilated heart failure with impaired coronary blood flow. New evidence also suggests that heart diseases trigger a reduction in cardiac tissue thyroid hormone levels, a condition that may not be detectible using serum hormone assays. Many animal and clinical studies have demonstrated a high prevalence of low thyroid function in heart diseases with worse outcomes from this condition. Animal and human studies have also demonstrated many benefits from thyroid hormone treatment of heart diseases, particularly heart failure. Nonetheless, this potential treatment has not yet translated to patients due to a number of important concerns. The most serious concern involves the potential of accidental overdose leading to increased arrhythmias and sudden death. Several important clinical studies, which actually used excessive doses of thyroid hormone analogs, have played a major role in convincing the medical community that thyroid hormones are simply too dangerous to be considered for treatment in cardiac patients. Nonetheless, this issue has not gone away due primarily to overwhelmingly positive evidence for treatment benefits and a new understanding of the cellular and molecular mechanisms underlying those benefits. This review will first discuss the clinical evidence for the use of thyroid hormones as a cardioprotective agent and then provide an overview of the cellular and molecular mechanisms underlying beneficial changes from thyroid hormone treatment of heart diseases. © 2016 American Physiological Society. Compr Physiol 6:1199-1219, 2016.

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

Cited by 36 publications

References 40 publications

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

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

Perfused Cells, Tissues and Organs by Magnetic Resonance Spectroscopy

Thyroid Hormone and Cardioprotection

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