Role of the murine thyroid hormone transporters Mct8 and Oatp1c1 in skeletal muscle, cardiovascular and metabolic system

小鼠甲状腺激素转运蛋白 Mct8 和 Oatp1c1 在骨骼肌、心血管和代谢系统中的作用

• 批准号: 280025311
• 负责人: Professorin Dr. Heike Heuer
• 金额: --
• 依托单位: Klinik für Endokrinologie und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280025311?language=en
• 关键词: Role; murine; thyroid; hormone; transporters

Thyroid hormone (TH) actions and metabolism are intracellular events that require the transport of TH across the plasma membrane. This process is facilitated by TH transporters of which the monocarboxylate transporter 8 (MCT8) has been most intensively studied. Inactivating mutations in the X-linked MCT8 gene are associated with a severe form of mental retardation and neuromuscular abnormalities. Another characteristic feature of this disease (also known as Allan-Herndon-Dudley syndrome (AHDS)) are highly elevated circulating T3 concentrations that in turn can cause thyrotoxic symptoms such as hypermetabolism, fat and muscle wasting as well as tachycardia. In order to unravel the exact underlying pathogenic mechanisms, we generated Mct8 ko mice that also lack the T4-specific transporter Oatp1c1. These Mct8/Oatp1c1 double knock-out (dko) mice show elevated serum T3 levels as the patients and a hypothyoid state in the CNS due to an impaired TH transport into the brain. Mct8/Oatp1c1 deficient mice also display learning and memory deficits as well as pronounced locomotor deficiencies, thus replicating the patients´ phenotype. Here, we aim to elucidate the consequences of murine Mct8 and/or Oatp1c1 deficiency on skeletal muscle innervation, function and regeneration. Our preliminary studies of Mct8/Oatp1c1 dko mice point to a distinct role of both transporters during activation and/or differentiation of satellite cells, the stem cells of the muscle. We therefore want to dissect the exact cell-specific function of Mct8 and Oatp1c1 during muscle regeneration by exploiting conditional knock-out mice. Another aim of our project is to determine the impact of a single or combined Mct8/Oatp1c1 deficiency on the cardiovascular and metabolic system. For this purpose, we will determine heart rate, body temperature and energy expenditure of TH transporter deficient mice at different ambient temperatures and will dissect systemic from tissue-autonomous effects by performing ex vivo studies as well as pharmacological deinnervation. Current efforts to treat patients with MCT8 mutations aim to use the TH analog Triac (TA3) to bypass the defective cellular import and to restore TH signaling particularly in the brain. It is, however, unclear, to which extent this treatment affects neuromuscular, cardiovascular and metabolic functions. We there aim to investigate the skeletal muscle, cardiovascular and metabolic consequences of TA3 treatment in Mct8/Oatp1c1 dko mice and to elucidate beneficial as well as side-effects of the treatment. Overall, we expect that our proposed studies will provide novel information regarding the pathogenic mechanisms underlying AHDS that are of immediate clinical relevance.

甲状腺激素（TH）的作用和代谢是细胞内的事件，需要运输TH跨质膜。这一过程是促进TH转运单羧酸转运蛋白8（MCT 8）已被最深入的研究。X连锁MCT 8基因的失活突变与严重的精神发育迟滞和神经肌肉异常有关。这种疾病（也称为Allan-Herndon-达德利综合征（AHDS））的另一个特征性特征是循环T3浓度高度升高，这进而可引起甲状腺毒性症状，如高代谢、脂肪和肌肉消耗以及心动过速。 为了解开确切的潜在致病机制，我们产生了Mct 8 ko小鼠，也缺乏T4特异性转运蛋白Oatp 1c 1。这些Mct 8/Oatp 1c 1双敲除（dko）小鼠显示出与患者相同的升高的血清T3水平和由于TH转运到脑中受损而导致的CNS中的甲状腺功能减退状态。Mct 8/Oatp 1c 1缺陷小鼠也表现出学习和记忆缺陷以及明显的运动缺陷，从而复制了患者的表型。 在这里，我们的目的是阐明小鼠Mct 8和/或Oatp 1c 1缺乏骨骼肌神经支配，功能和再生的后果。我们对Mct 8/Oatp 1c 1 dko小鼠的初步研究表明，这两种转运蛋白在卫星细胞（肌肉干细胞）的活化和/或分化过程中发挥着不同的作用。因此，我们希望通过利用条件性基因敲除小鼠来剖析Mct 8和Oatp 1c 1在肌肉再生过程中的确切细胞特异性功能。我们项目的另一个目的是确定单一或联合Mct 8/Oatp 1c 1缺乏对心血管和代谢系统的影响。 为此，我们将确定心率，体温和TH转运蛋白缺陷小鼠在不同的环境温度下的能量消耗，并将解剖系统从组织自主的影响进行离体研究，以及药理学去神经支配。 目前治疗MCT 8突变患者的努力旨在使用TH类似物三端双向可控硅开关（TA 3）绕过有缺陷的细胞输入并恢复TH信号传导，特别是在大脑中。然而，目前尚不清楚这种治疗在多大程度上影响神经肌肉，心血管和代谢功能。我们的目的是研究Mct 8/Oatp 1c 1 dko小鼠中TA 3治疗的骨骼肌、心血管和代谢后果，并阐明治疗的有益作用和副作用。总体而言，我们期望我们提出的研究将提供新的信息，致病机制的基础AHDS是直接的临床意义。