Myocardial Retinoid X Receptor, Thyroid Hormone Receptor, and Myosin Heavy Chain Gene Expression in the Rat During Adult Aging

Abstract

Although previous studies have shown that cardiac myosin heavy chain (MHC) composition undergoes a switch from the alpha- to beta-isoform in the heart during adult aging, the underlying mechanisms responsible for this switch are unknown. Cardiac MHC gene expression is regulated, in part, by thyroid hormone responsive elements present in the regulatory control regions of the alpha- and beta-MHC genes. Age-associated changes in the expression of thyroid hormone receptors (THRs) and/or retinoid X receptors (RXRs), the heterodimeric partner for THRs, could explain the age-associated changes in MHC expression. Accordingly, we measured mRNA levels for the cardiac muscle MHCs and the rat THR and RXR genes in the left ventricles of Wistar rats at 2, 6, and 24 months of age. Although there were no significant changes in RXR alpha or RXR beta mRNA levels with age, both alpha 1 and alpha 2 THR mRNA levels decreased significantly between 2 and 6 months of age. During this same time period, the mRNA levels for alpha-MHC declined by more than half, whereas beta-MHC mRNA levels remained low and unchanged. On the other hand, between 6 and 24 months, when mRNA levels for beta-MHC increased and alpha-MHC continued to decrease, there was a significant decline in THR beta 1 and RXR gamma mRNA levels accompanied by a reduction in the THR beta 1 and RXR gamma protein levels. These data show a pattern of change that suggests that the decline in alpha-MHC gene expression may be biphasic and due to a decline in alpha 1 (and possibly alpha 2) THR levels between 2 and 6 months of age and a decline in THR beta 1 and RXR gamma levels at later stages. In contrast, the increase in beta-MHC gene expression was associated only with the changes in THR beta 1 and RXR gamma mRNA and protein levels.

The effects of caloric restriction and age on thyroid hormone signalling in the heart of rats

“…In a study conducted on Wistar rats, cardiac THRα1 declined between 2 and 6 months of age, and THRβ between 6 and 24 months of age (Long et al, 1999). Our results are not in conflict with these observations.…”

Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction

“…Unchanged DHPR-α and β-MHC seem to rule out contribution from L-type Ca 2+ channel and myosin isozyme switch in cardiomyocyte dysfunction under the present experimental setting. Somewhat conflicting data have been seen for expression or function of cardiac Ca 2+ , K + channels and MHC isozyme under senescence including augmented (Dibb et al 2004;Schuyler and Yarbrough 1990), unchanged (Josephson et al 2002;Krishnamurthy et al 2004;Long et al 1999) or depressed (Liu et al 2000;Long et al 1999;Ranki et al 2002) Ca 2+ or K + channel expression as well as β-MHC distribution. Animal species, strains, gender and experimental conditions may play significant roles in these discrepant findings.…”

Regulation of Thyroid Hormone Receptor Isoforms in Physiological and Pathological Cardiac Hypertrophy

“…In the aging rat, increased ␤-MyHC transcription correlates with decreased TR␤1 levels and reduced ␣-MyHC correlates with reduced TR␣1. 23 A correlation between levels of TR␣1 and ␣-MyHC is also seen in the failing human heart. 24 A preferential effect of GC-1 on myocardial SERCA and ␤-MyHC is not seen in the rat in vivo, but this might be because of lower bioavailability of GC-1 in cardiac tissue.…”

“…Recent studies in the aging rat and in human end-stage heart failure reveal changes in myocardial TR levels that correlate with changes in TH target gene transcription. 23,24 However, possible changes in TR levels in hypertrophy have not been examined, and TR functions on target promoters in myocytes have not been compared. We measured TRs in rat hypertrophy models in culture and in vivo and tested TR functions in culture using transfection and treatment with T3 or a TR␤1-selective agonist.…”