Differential expression of thyroid hormone receptor isoforms is strikingly related to cardiac and skeletal muscle phenotype during postnatal development

Abstract

The genomic actions of thyroid hormones (THs) are mediated by receptors (TRs) that are encoded by two protooncogenes, c-erbA-α and c-erbA-β. The precise functions of the TR isoforms are unclear and this study focuses on the potential roles of the TRα and TRβ isoforms in mammalian striated muscles postnatally. The porcine TRαl, TRα2 and TRβ1 cDNAs were first cloned, sequenced and characterised by Northern blotting. A quantitative analysis of TR isoform expression was then undertaken, using RNase protection analysis with novel riboprobes designed to detect relative expression levels of TRα1, TRα2, TRβ1 and TRβ2, in functionally distinct muscles from 7- week-old pigs kept under controlled conditions of nutrition and thermal environment. We found a striking muscle-specific pattern of TRα isoform distribution: in heart the mRNA level of TRα2 (non-TH binding) was markedly greater (P<0.01) than that of TRαl (TH binding); in longissimus dorsi the opposite pattern of expression occurred (TRαl>TRα2, P<0.001); in soleus, diaphragm and rhomboideus there were no differences between the two isoforms. The overall abundance of TRβ was very much lower than that of TRα, and TRβ1 was expressed at a higher level than TRβ2 in all muscles. Together with recent data from TR gene inactivation studies and the established role of TH in determining myosin heavy chain isoform expression and muscle phenotype, these results suggest a role for differential expression of TR isoforms in acquisition and maintenance of optimal cardiac and skeletal muscle function.