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

Abstract

Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3′-triiodothyronine (T₃). T₃acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T₃receptors (TRs). The diverse function of T₃is presumed to be mediated by TR-α₁and TR-β, 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 T₃regulates the expression of specific MHC isoforms via distinct TRs. In fast-twitch extensor digitorum longus (EDL) muscle, TR-α₁-, TR-β-, or TR-α₁β-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 β/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-β had no significant effect on the expression of MHC isoforms. An increase ( P < 0.05) of type I MHC was observed in the TR-α₁-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-α₁β-deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-α₁β-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 β/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-α₁and TR-β 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.