Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
Bioprocessing Technology Institute, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
Front Endocrinol (Lausanne). 2021 Apr 20;12:653557. doi: 10.3389/fendo.2021.653557. eCollection 2021.
Insulin and muscle contractions mediate glucose transporter 4 (GLUT4) translocation and insertion into the plasma membrane (PM) for glucose uptake in skeletal muscles. Muscle contraction results in AMPK activation, which promotes GLUT4 translocation and PM insertion. However, little is known regarding AMPK effectors that directly regulate GLUT4 translocation. We aim to identify novel AMPK effectors in the regulation of GLUT4 translocation. We performed biochemical, molecular biology and fluorescent microscopy imaging experiments using gain- and loss-of-function mutants of tropomodulin 3 (Tmod3). Here we report Tmod3, an actin filament capping protein, as a novel AMPK substrate and an essential mediator of AMPK-dependent GLUT4 translocation and glucose uptake in myoblasts. Furthermore, Tmod3 plays a key role in AMPK-induced F-actin remodeling and GLUT4 insertion into the PM. Our study defines Tmod3 as a key AMPK effector in the regulation of GLUT4 insertion into the PM and glucose uptake in muscle cells, and offers new mechanistic insights into the regulation of glucose homeostasis.
胰岛素和肌肉收缩介导葡萄糖转运蛋白 4（GLUT4）向骨骼肌质膜（PM）的易位和插入，以摄取葡萄糖。肌肉收缩导致 AMPK 激活，促进 GLUT4 易位和 PM 插入。然而，关于直接调节 GLUT4 易位的 AMPK 效应物知之甚少。我们旨在确定调节 GLUT4 易位的新型 AMPK 效应物。我们使用肌动蛋白丝加帽蛋白 tropomodulin 3（Tmod3）的功能获得和功能丧失突变体进行了生化、分子生物学和荧光显微镜成像实验。在这里，我们报告了 Tmod3 作为一种新型的 AMPK 底物和 AMPK 依赖性 GLUT4 易位和葡萄糖摄取的必需介质，在肌母细胞中发挥作用。此外，Tmod3 在 AMPK 诱导的 F-肌动蛋白重塑和 GLUT4 插入 PM 中起关键作用。我们的研究将 Tmod3 定义为调节 PM 中 GLUT4 插入和肌肉细胞中葡萄糖摄取的关键 AMPK 效应物，并为葡萄糖稳态的调节提供了新的机制见解。
