Developmental expression analysis of thyroid hormone receptor isoforms reveals new insights into their essential functions in cardiac and skeletal muscles

ABSTRACT Nuclear thyroid hormone (TH) receptors (TR) play a critical role in mediating the diverse actions of TH in development, differentiation, and metabolism of most tissues, but the role of TR isoforms in muscle development and function is unclear. Therefore, we have undertaken a comprehensive expression analysis of TRα 1, TRβ 1, TRβ 2 (TH binding), and TRα 2 (non‐TH binding) in functionally distinct porcine muscles during prenatal and postnatal development. Use of a novel and highly sensitive RNase protection assay revealed striking muscle‐specific developmental profiles of all four TR isoform mRNAs in cardiac, longissimus, soleus, rhomboideus, and diaphragm. Distribution of TR isoforms varied markedly between muscles;TR α expression was considerably greater than TRβ and there were significant differences in the ratios TRα 1:TR α 2, and TRβ 1:TRβ 2. Together with immunohistochemistry of myosin heavy chain isoforms and data on myogenesis and maturation of the TH axis, these findings provide new evidence that highlights central roles for 1) TRα isoforms in fetal myogenesis, 2) the ratio TRα 1:TR α 2 in determining cardiac and skeletal muscle phenotype and function; 3) TRβ in maintaining a basal level of cellular response to TH throughout development and a specific maturational function around birth. These findings suggest that events disrupting normal developmental profiles of TR isoforms may impair optimal function of cardiac and skeletal muscles.—White, P., Burton, K. A., Fowden, A. L., Dauncey, M. J. Developmental expression analysis of thyroid hormone receptor isoforms reveals new insights into their essential functions in cardiac and skeletal muscles. FASEB J. 15, 1367–1376 (2001)