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TRs Have Common and Isoform-Specific Functions in Regulation of the Cardiac Myosin Heavy Chain Genes

Department of Cell and Molecular Biology (A.M., B.V.) and Department of Clinical Neuroscience (F.U., L.L.), Karolinska Institute, S-171 77 Stockholm, Sweden, Noll Physiological Research Center and Department of Cellular and Molecular Physiology (F.U., L.L.), Pennsylvania State University, University Park, Pennsylvania 16802; and Department of Human Genetics (D.F.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Bjorn Vennstrom, Department of Cell and Molecular Biology, Karolinska Institute, Room D427, Doktorsringen 2D, Soina, Sweden S-171 77. E-mail: bjorn.vennstrom{at}cmb.ki.se

TR1 and TRß mediate the regulatory effects of T₃ and have profound effects on the cardiovascular system. We have analyzed the expression of the cardiac myosin heavy chain (MyHC) genes and ß in mouse strains deficient for one or several TR genes to identify specific regulatory functions of TR1 and TRß. The results show that TR1 deficiency, which slows the heart rate, causes chronic overexpression of MyHCß. However, MyHCß was still suppressible by T₃ in both TR1- and TRß-deficient mice, indicating that either receptor can mediate repression of MyHCß. T₃-dependent induction of the positively regulated MyHC gene was similar in both TR1- and TRß-deficient mice. The data identify a specific role for TR1 in the negative regulation of MyHCß, whereas TR1 and TRß appear interchangeable for hormone-dependent induction of MyHC. This suggests that TR isoforms exhibit distinct specificities in the genes that they regulate within a given tissue type. Thus, dysregulation of MyHCß is likely to contribute to the critical role of TR1 in cardiac function.

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