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J. Biol. Chem., Vol. 279, Issue 39, 40699-40706, September 24, 2004

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Disruption of Cortical Actin in Skeletal Muscle Demonstrates an Essential Role of the Cytoskeleton in Glucose Transporter 4 Translocation in Insulin-sensitive Tissues^*

Joseph T. Brozinick, Jr., Eric D. Hawkins, Andrew B. Strawbridge¶, and Jeffrey S. Elmendorf¶||

From the Eli Lilly and Company, Indianapolis, Indiana 46285 and the Departments of ^¶Cellular & Integrative Physiology and ^||Biochemistry & Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana 46202

Cell culture work suggests that signaling to polymerize cortical filamentous actin (F-actin) represents a required pathway for the optimal redistribution of the insulin-responsive glucose transporter, GLUT4, to the plasma membrane. Recent in vitro study further suggests that the actin-regulatory neural Wiskott-Aldrich syndrome protein (N-WASP) mediates the effect of insulin on the actin filament network. Here we tested whether similar cytoskeletal mechanics are essential for insulin-regulated glucose transport in isolated rat epitrochlearis skeletal muscle. Microscopic analysis revealed that cortical F-actin is markedly diminished in muscle exposed to latrunculin B. Depolymerization of cortical F-actin with latrunculin B caused a time- and concentration-dependent decline in 2-deoxyglucose transport. The loss of cortical F-actin and glucose transport was paralleled by a decline in insulin-stimulated GLUT4 translocation, as assessed by photolabeling of cell surface GLUT4 with Bio-LC-ATB-BMPA. Although latrunculin B impaired insulin-stimulated GLUT4 translocation and glucose transport, activation of phosphatidylinositol 3-kinase and Akt by insulin was not rendered ineffective. In contrast, the ability of insulin to elicit the cortical F-actin localization of N-WASP was abrogated. These data provide the first evidence that actin cytoskeletal mechanics are an essential feature of the glucose transport process in intact skeletal muscle. Furthermore, these findings support a distal actin-based role for N-WASP in insulin action in vivo.

Received for publication, March 10, 2004 , and in revised form, June 21, 2004.

^* This work was supported by National Center for Complementary and Alternative Medicine Grant AT001846 (to J. S. E.), American Diabetes Foundation Career Development Award 60779 (to J. S. E.), and an American Heart Association Midwest Affiliate Predoctoral Fellowship (to A. B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Eli Lilly and Co., Lilly Corporate Center, Drop Code 0545, Indianapolis, IN 46285. Tel.: 317-277-1155; Fax: 317-276-9574; E-mail: brozinick_joseph_t{at}lilly.com.

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