Leibniz Institute on Aging/Fritz Lipmann Institute, Jena, Germany; Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Leibniz Institute on Aging/Fritz Lipmann Institute, Jena, Germany.
Stem Cell Reports. 2018 Jun 5;10(6):1959-1974. doi: 10.1016/j.stemcr.2018.03.021. Epub 2018 Apr 26.
Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis.
甲状腺激素（TH）转运蛋白是 TH 在靶细胞中跨膜转运所必需的。在人类中，TH 转运蛋白 MCT8 的失活突变导致 Allan-Herndon-Dudley 综合征，其特征为严重的神经肌肉症状和异常的 TH 血清谱，这在 Mct8 敲除小鼠和 Mct8/Oatp1c1 双敲除（M/O DKO）小鼠中得到完全复制。对组织 TH 含量和 TH 调节基因表达的分析表明，Mct8 缺陷骨骼肌处于甲状腺毒症状态。两种 TH 转运蛋白在激活的卫星细胞（SCs）中均上调。在 M/O DKO 小鼠中，我们观察到分化的 SC 数量明显减少，表明干细胞功能受损。此外，缺乏两种转运蛋白的 M/O DKO 小鼠和仅在 SC 中缺乏两种转运蛋白的小鼠表现出受损的骨骼肌再生。我们的数据为 MCT8 和 OATP1C1 在 SC 激活中的独特守门员功能提供了确凿的证据，强调了在肌发生过程中精细调节 TH 信号的重要性。
