Abstract
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.
Highlights
In addition to insulin stimulation, energy demanding conditions enhance glucose transport in skeletal muscle through glucose transporter 4 (GLUT4) redistribution to the plasma membrane (PM) through a distinct but separate signaling cascade other than insulin-signaling in skeletal muscle [1]
GLUT4 translocation to the cell surface includes at least two steps: first, GLUT4 trafficking from the intracellular space to near the PM; and second, GLUT4 insertion into the PM, which results in the surface exposure of its exofacial loops
Similar to insulin signaling activation, significant increase in GLUT4 translocation to the PM and surface exposure was observed upon 5’ adenosine monophosphate-activated protein kinase (AMPK) activation, along with increased glucose uptake in both L6
Summary
In addition to insulin stimulation, energy demanding conditions enhance glucose transport in skeletal muscle through GLUT4 redistribution to the plasma membrane (PM) through a distinct but separate signaling cascade other than insulin-signaling in skeletal muscle [1]. When there is reduced energy supply in muscle cells under certain conditions like muscle contraction and deprivation of glucose or oxygen, glucose is replenished under the regulation of AMPK signaling [2]. AMPK acts as a sensor of cellular energy status in eukaryotic cells [3]. It is activated by increased cellular [AMP]/[ATP] ratio caused by metabolic stresses, which accelerates ATP consumption and/or interferes with ATP production [4]. AMPK activation in skeletal muscle correlates with enhanced glucose uptake [5, 6]. AMPK activators, such as AICAR, adiponectin, IL-6, dinitrophenol and A-769662 promote GLUT4 trafficking to the cell surface and enhance glucose uptake in myotubes [7, 8]
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