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Heterotypic endosomal fusion as an initial trigger for insulin‐induced GLUT4 translocation in skeletal muscle

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The Journal of Physiology

Published online on

Abstract

Skeletal muscle is the major systemic glucose disposal site. Both insulin and exercise facilitate translocation of the glucose transporter GLUT4 via distinct signalling pathways, and exercise enhances insulin sensitivity. However, trafficking mechanisms controlling GLUT4 mobilization in skeletal muscle remain poorly understood due to technical limitations. Herein, employing various imaging techniques on isolated skeletal myofibers, we show that one of the initial triggers of insulin‐induced GLUT4 translocation is heterotypic endomembrane fusion arising from very small static GLUT4‐containing vesicles with a subset of transferrin receptor‐containing endosomes. Importantly, pretreatment with exercise‐mimetic stimuli potentiated the susceptibility to insulin responsiveness as evidenced by these acute endomembranous activities. We also found that AS160 exhibited stripe‐like localization nearby sarcomeric α‐actinin and that insulin induced a reduction of the stripe‐like localization accompanying with changes in its detergent solubility. Our results thus provide a conceptual framework indicating that GLUT4 protein trafficking via heterotypic fusion is a critical feature of GLUT4 translocation in skeletal muscles and also suggest that the efficacy of the endomembranous fusion process in response to insulin is involved in exercise benefits. This article is protected by copyright. All rights reserved