Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles.
Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles.
复制标题
DOI：
10.1152/ajpregu.2000.278.6.r1545
复制
发表时间：
2000-06
期刊：
影响因子：
--
通讯作者：
Fushun Yu;Fushun Yu;S. Göthe;Lilian Wikström;Douglas Forrest;Björn Vennström;Lars Larsson;
中科院分区：
文献类型：
--
作者：
Fushun Yu;Fushun Yu;S. Göthe;Lilian Wikström;Douglas Forrest;Björn Vennström;Lars Larsson;
已知骨骼肌是甲状腺激素活性代谢物（即 3,5,3'-三碘甲状腺原氨酸 (T(3))）的靶标。 T(3) 通过 T(3) 受体 (TR) 抑制或激活编码不同肌球蛋白重链 (MHC) 亚型的基因发挥作用。 T(3) 的多种功能被认为是由 TR-α(1) 和 TR-β 介导的，但特定 TR 在调节 MHC 同工型表达中的功能仍不清楚。在这项研究中，TR 缺陷小鼠被用来扩展我们对 T(3) 通过不同 TR 调节特定 MHC 同工型表达的机制的了解。在快缩趾长伸肌 (EDL) 中，TR-α(1)、TR-β 或 TR-α(1)β 缺陷小鼠的 IIB 型 MHC 含量出现小幅但具有统计学意义的下降 (P < 0.05)，而 I 型纤维数量则有所增加。在慢肌比目鱼肌中，TR 缺陷小鼠中的 β/慢 MHC（I 型）亚型显着上调 (P < 0. 001)，但这种效应高度依赖于缺失的受体类型。 TR-β的缺乏对MHC亚型的表达没有显着影响。在 TR-α(1) 缺陷的肌肉中观察到 I 型 MHC 增加 (P < 0.05)。在 TR-α(1)β 缺陷小鼠中观察到慢速 I 型 MHC 的显着过度表达 (P < 0.001) 和快速 IIA 型 MHC 的相应下调 (P < 0.001)。 TR-α(1)β缺陷小鼠中MHC同种型表达的肌肉和纤维特异性差异类似于甲状腺功能减退动物中报告的MHC同种型转变，即EDL中的轻度MHC转变，比目鱼肌中β/慢MHC同种型的显着但不完全上调，以及不同比目鱼肌纤维中对TR缺乏的可变反应。因此，在缺乏甲状腺激素或缺乏甲状腺激素受体的情况下，对肌肉的影响是相似的，表明 TR-α(1) 和 TR-β 共同介导 T(3) 的已知作用。然而，甲状腺激素如何在其作用中发挥肌肉和肌纤维特异性作用仍不清楚。最后，虽然本研究没有专门研究发育性 MHC 转变，但 TR 缺陷小鼠中胚胎和胎儿 MHC 同工型的缺乏表明，最终向成人 MHC 同工型的转变不仅仅由 TR 介导。
Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3'-triiodothyronine (T(3)). T(3) acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T(3) receptors (TRs). The diverse function of T(3) 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 T(3) 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(1)beta-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(1)beta-deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-alpha(1)beta-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 T(3). 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.