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Am J Physiol Regul Integr Comp Physiol 278: R1545-R1554, 2000;
0363-6119/00 $5.00
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Vol. 278, Issue 6, R1545-R1554, June 2000

Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles

Fushun Yu1,2, Sten Göthe3, Lilian Wikström3, Douglas Forrest4, Björn Vennström3, and Lars Larsson1,2

1 Noll Physiological Research Center and Department of Cellular and Molecular Physiology, Pennsylvania State University, University Park, Pennsylvania 16802-6900; 2 Department of Clinical Neuroscience, Karolinska Institute/Karolinska Hospital, 171 76 Stockholm; 3 Laboratory of Developmental Biology, Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden; and 4 Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029

Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3'-triiodothyronine (T3). T3 acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T3 receptors (TRs). The diverse function of T3 is presumed to be mediated by TR-alpha 1 and TR-beta , but the function of specific TRs in regulating MHC isoform expression has remained undefined. In this study, TR-deficient mice were used to expand our knowledge of the mechanisms by which T3 regulates the expression of specific MHC isoforms via distinct TRs. In fast-twitch extensor digitorum longus (EDL) muscle, TR-alpha 1-, TR-beta -, or TR-alpha 1beta -deficient mice showed a small but statistically significant decrease (P < 0.05) of type IIB MHC content and an increased number of type I fibers. In the slow-twitch soleus, the beta /slow MHC (type I) isoform was significantly (P < 0.001) upregulated in the TR-deficient mice, but this effect was highly dependent on the type of receptor deleted. The lack of TR-beta had no significant effect on the expression of MHC isoforms. An increase (P < 0.05) of type I MHC was observed in the TR-alpha 1-deficient muscle. A dramatic overexpression (P < 0.001) of the slow type I MHC and a corresponding downregulation of the fast type IIA MHC (P < 0.001) was observed in TR-alpha 1beta -deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-alpha 1beta -deficient mice resembled the MHC isoform transitions reported in hypothyroid animals, i.e., a mild MHC transition in the EDL, a dramatic but not complete upregulation of the beta /slow MHC isoform in the soleus, and a variable response to TR deficiency in different soleus muscle fibers. Thus the consequences on muscle are similar in the absence of thyroid hormone or absence of thyroid hormone receptors, indicating that TR-alpha 1 and TR-beta together mediate the known actions of T3. However, it remains unknown how thyroid hormone exerts muscle- and muscle fiber-specific effects in its action. Finally, although developmental MHC transitions were not studied specifically in this study, the absence of embryonic and fetal MHC isoforms in the TR-deficient mice indicates that ultimately the transition to the adult MHC isoforms is not solely mediated by TRs.

3,5,3'-triiodothyronine receptor deficiency, myosin heavy chain, enzyme histochemistry; electrophoresis; soleus muscle; extensor digitorum longus muscle


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