title: Extra-nuclear telomerase reverse transcriptase (TERT) regulates glucose transport in skeletal muscle cells.
abstract: 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.
authors: Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK. Electronic address: Fozia.Shaheen@warwick.ac.uk.
authors: Fozia
authors: F
authors: Shaheen
authors: Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK. Electronic address: d.grammatopoulos@warwick.ac.uk.
authors: Dimitris K
authors: DK
authors: Grammatopoulos
authors: Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK. Electronic address: Jurgen.Muller@warwick.ac.uk.
authors: Jürgen
authors: J
authors: Müller
authors: Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, CV2 2DX, UK. Electronic address: V.A.Zammit@warwick.ac.uk.
authors: Victor A
authors: VA
authors: Zammit
authors: 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. Electronic address: Hendrik.Lehnert@uk-sh.de.
authors: Hendrik
authors: H
authors: Lehnert
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; C509186:TERT protein, human; D019098:Telomerase; D005947:Glucose
keywords: Ageing; Diabetes; Glucose transporter; Insulin; Muscle; TERT