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 hormone also mediates changes in myocardial energy metabolism. Thyroid receptor dysfunction may limit the heart's 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. Exercise conditioning in these aged rats alters the mRNA expression for TR regulated genes such as myosin heavy chain alpha and beta, and sarcoplasmic reticulum 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 associated with some states in the aged, such as subclinical hypothyroidism. 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 heart's 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 have fully characterized myocardial metabolism in a transgenic mouse expressing a dominant negative cardiac selective mutation in TR?1 and documented abnormal fatty acid metabolism in heart of aged non-transgenic littermates. We will use an aging mouse model, which manifests mild reductions in plasma total T3 levels to test the primary hypothesis that thyroid hormone mediates the metabolic phenotype in the aging heart. The proposed studies in response to PA-08-38 (Thyroid in Aging) will establish the basis for further studies, which would examine the molecular mechanisms of thyroid action, and determine if metabolic action by thyroid hormone can modify the cardiomyopathy of aging.
This proposal is in response to PA-08-308 """"""""Thyroid in Aging"""""""". We will evaluate thyroid hormone's role in controlling substrate (fuel) use in the aging heart. These studies will serve as background data for more elaborate mechanistic studies in the future.
| Ledee, Dolena; Portman, Michael A; Kajimoto, Masaki et al. (2013) Thyroid hormone reverses aging-induced myocardial fatty acid oxidation defects and improves the response to acutely increased afterload. PLoS One 8:e65532 |
