Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging

Although previous studies have shown that cardiac myosin heavy chain (MHC) composition undergoes a switch from the α- to β-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 α- and β-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 RXRα or RXRβ mRNA levels with age, both α1 and α2 THR mRNA levels decreased significantly between 2 and 6 months of age. During this same time period, the mRNA levels for α-MHC declined by more than half, whereas β- MHC mRNA levels remained low and unchanged. On the other hand, between 6 and 24 months, when mRNA levels for β-MHC increased and α-MHC continued to decrease, there was a significant decline in THRβ1 and RXRγ mRNA levels accompanied by a reduction in the THRβ1 and RXRγ protein levels. These data show a pattern of change that suggests that the decline in α-MHC gene expression may be biphasic and due to a decline in α1 (and possibly α2) THR levels between 2 and 6 months of age and a decline in THRβ1 and RXRγ levels at later stages. In contrast, the increase in β-MHC gene expression was associated only with the changes in THRβ1 and RXRγ mRNA and protein levels.