Thyroid Hormone and Myocardial Substrate Use with Aging
EMSL Project ID
30417
Abstract
Thyroid hormone regulates cardiac function through binding to its nuclear receptors (TRs). Classically, the ligand bound receptors in turn bind to response elements and control transcription of key cardiac genes. A decrease in triiodothyronine-TR binding, such as occurs in systemic hypothyroidism, certain resistance to thyroid hormone syndromes (RTH), or in various transgenic mouse models adversely effects cardiac function. Changes in TR ligand binding capacity have also been reported in failing human hearts. Although, this cardiac dysfunction occurs in part through alterations in excitation-contraction and transport proteins, the data from our laboratory indicate that thyroid also mediates changes in myocardial energy metabolism. Thyroid receptor dysfunction may limit the hearts ability to shift substrate pathways and provide adequate energy supply during stress responses. Chronic or intermittent energy starvation during these stress periods could contribute to abnormal compensatory processes and/or cardiomyocyte damage. Recent data from other laboratories indicate that exercise training in aged rats promoted improved cardiac function in association with elevated expression and binding capacity of thyroid hormone receptors. The mRNA expression alters for TR regulated genes such as myosin heavy chain alpha and beta, and sarcoplasmic reticulum with exercise conditioning in these aged rats in a manner suggesting mediation by thyroid hormone. Presumably, thyroid mediated signaling pathways triggered by exercise conditioning return senescent heart function to levels similar to those measured in much younger hearts. These data strongly imply that thyroid receptor dysregulation participates in cardiomyopathy of aging. Although the primary genes previously under study were those regulating proteins involved in excitation contraction, the investigators also showed that proteins regulating cardiac metabolism such as retinoid X receptors are altered by exercise conditioning in these aged rats. Changes in metabolic signaling pathways might explain why the aging rat heart lacks the ability to modify substrate uptake in response to varying nutritional conditions. In particular, increasing fatty acid supply does not inhibit glucose uptake, suggesting that the myocardial -oxidation capability is limited by aging, and that the aging hearts substrate oxidative capacity restricts responses to stress or exercise. Thus, alterations in myocardial remodeling triggered by thyroid hormone signaling in aged hearts may be caused primarily by changes in metabolism. We propose studying thyroid hormone receptor regulation of cardiac metabolism during aging in a transgenic mouse expressing a dominant negative cardiac selective mutation in TR1. This natural occurring 337T human mutation from patients with resistance to thyroid hormone renders the receptor non-ligand binding. Our specific aims are: 1) Determine if aging modifies substrate flux in the normal mouse heart
2) Determine if thyroid hormone treatment ameliorates these age related modifications in substrate flux
3) If thyroid hormone ameliorates these age induced cardiac metabolic abnormalities, determine if thyroid receptor dysfunction limits this response, or if thyroid action does not involve thyroid receptor.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2008-10-01
End Date
2011-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
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Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H868-75. Epub 2010 Jul 2.
Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice.
Hyyti OM, Ledee D, Ning XH, Ge M, Portman MA.
SourceDivision of Cardiology and Department of Pediatrics, University of Washington, and Seattle Childrens Hospital Research Institute, Center for Developmental Therapeutics, Seattle, Washington, USA.
Abstract
Hyyti OM, A Olson, M Ge, XH Ning, NE Buroker, Y Chung, T Jue, and MA Portman. 2008. "Cardioselective Dominant-negative Thyroid Hormone Receptor (?337T) Modulates Myocardial Metabolism and Contractile Dfficiency." American Journal of Physiology 295:E420-E427. doi:doi:10.1152/ajpendo.90329.2008
Hyyti OM, D Ledee, XH Ning, M Ge, and MA Portman. 2010. "Aging Impairs Myocardial Fatty Acid and Ketone Oxidation and Modifies Cardiac Functional and Metabolic Responses to Insulin in Mice." American Journal of Physiology. Heart and Circulatory Physiology 299:H868-H875. doi:doi:10.1152/ajpheart.00931.2009
Olson A, B Bouchard, XH Ning, NG Isern, C Des Rosiers, and MA Portman. 2012. "TRIIODOTHYRONINE INCREASES MYOCARDIAL FUNCTION AND PYRUVATE ENTRY INTO THE CITRIC ACID CYCLE AFTER REPERFUSION IN A MODEL OF INFANT CARDIOPULMONARY BYPASS ." American Journal of Physiology. Heart and Circulatory Physiology 302(5):H1086-H1093.
Olson A, DR Ledee, PhD, K Iwamoto, M Kajimoto, CM O'Kelly-Priddy, NG Isern, and MA Portman. 2012. "C-Myc Induced Compensated Cardiac Hypertrophy Increases Free Fatty Acid Utilization for the Citric Acid Cycle." Journal of Molecular and Cellular Cardiology.
Olson A, OM Hyyti, GA Cohen, XH Ning, M Sadilek, NG Isern, and MA Portman. 2008. "Superior Cardiac Function Via Anaplerotic Pyruvate in the Immature Swine Heart After Cardiopulmonary Bypass and Reperfusion." American Journal of Physiology. Heart and Circulatory Physiology 295(6):H2315-H2320. doi:10.1152/ajpheart.00739.2008