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.

Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma

“…The study on TERT knockout mice reveals that telomere dysfunction is associated with decreased gluconeogenesis [36]. Furthermore, another study demonstrates that extra-nuclear TERT is associated with glucose transporters and regulated glucose transport [37]. Therefore, we hypothesize that the elevated cytoplasmic TERT in CCHCC is responding to abnormal glucose or lipid metabolism, thereby inhibiting cell apoptosis and promoting cancer cell survival.…”

Telomere attrition and diabetes mellitus

“…18 Furthermore, a recent in vitro study has shown that inhibition of TERT expression in muscle cells reduced their basal glucose uptake, whereas overexpression of TERT significantly increased their glucose uptake. 58 However, this effect of TERT occurs outside the nucleus through direct interaction of TERT with glucose transporters, and the effect of myocyte telomere shortening or elongation on insulin sensitivity should be examined further.…”

Means to the ends: The role of telomeres and telomere processing machinery in metastasis

“…Mitochondrial function is also reliant on both expression and subcellular localization of TERT, whose association with mitochondria protects cells from oxidative stress [126]. As such, TERT activation may serve to stimulate mitochondrial biogenesis concomitant with increased glucose uptake and utilization [127, 128]. This holds functional significance, as reactive oxygen species (ROS) within primary tumor microenvironments can induce DNA mutations that instill cancer cells with a growth advantage [129], while systemic ROS production serves as a defense against cancer cell dissemination [130].…”