Shaheen Fozia, Grammatopoulos Dimitris K, Müller Jürgen, Zammit Victor A, Lehnert Hendrik
Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK.
Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK; First Department of Medicine, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Biochim Biophys Acta. 2014 Sep;1842(9):1762-9. doi: 10.1016/j.bbadis.2014.06.018. Epub 2014 Jun 23.
Telomerase reverse transcriptase (TERT) is a key component of the telomerase complex. By lengthening telomeres in DNA strands, TERT increases senescent cell lifespan. Mice that lack TERT age much faster and exhibit age-related conditions such as osteoporosis, diabetes and neurodegeneration. Accelerated telomere shortening in both human and animal models has been documented in conditions associated with insulin resistance, including T2DM. We investigated the role of TERT, in regulating cellular glucose utilisation by using the myoblastoma cell line C2C12, as well as primary mouse and human skeletal muscle cells. Inhibition of TERT expression or activity by using siRNA (100nM) or specific inhibitors (100nM) reduced basal 2-deoxyglucose uptake by ~50%, in all cell types, without altering insulin responsiveness. In contrast, TERT over-expression increased glucose uptake by 3.25-fold. In C2C12 cells TERT protein was mostly localised intracellularly and stimulation of cells with insulin induced translocation to the plasma membrane. Furthermore, co-immunoprecipitation experiments in C2C12 cells showed that TERT was constitutively associated with glucose transporters (GLUTs) 1, 4 and 12 via an insulin insensitive interaction that also did not require intact PI3-K and mTOR pathways. Collectively, these findings identified a novel extra-nuclear function of TERT that regulates an insulin-insensitive pathway involved in glucose uptake in human and mouse skeletal muscle cells.
端粒酶逆转录酶（TERT）是端粒酶复合物的关键组成部分。通过延长DNA链中的端粒，TERT可延长衰老细胞的寿命。缺乏TERT的小鼠衰老速度更快，并表现出与年龄相关的病症，如骨质疏松症、糖尿病和神经退行性变。在包括2型糖尿病在内的与胰岛素抵抗相关的病症中，人类和动物模型中均已记录到端粒加速缩短的情况。我们使用成肌细胞瘤细胞系C2C12以及原代小鼠和人类骨骼肌细胞，研究了TERT在调节细胞葡萄糖利用中的作用。使用小干扰RNA（100nM）或特异性抑制剂（100nM）抑制TERT表达或活性，在所有细胞类型中均可使基础2-脱氧葡萄糖摄取降低约50%，且不改变胰岛素反应性。相比之下，TERT过表达使葡萄糖摄取增加了3.25倍。在C2C12细胞中，TERT蛋白大多定位于细胞内，胰岛素刺激细胞可诱导其向质膜转位。此外，C2C12细胞中的免疫共沉淀实验表明，TERT通过一种不依赖胰岛素的相互作用与葡萄糖转运蛋白（GLUT）1、4和12组成性结合，这种相互作用也不需要完整的PI3-K和mTOR信号通路。总的来说，这些发现确定了TERT一种新的核外功能，该功能调节参与人类和小鼠骨骼肌细胞葡萄糖摄取的不依赖胰岛素的信号通路。
