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Diabetes 55:2067-2076, 2006
DOI: 10.2337/db06-0150
© 2006 by the American Diabetes Association
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Distinct Signals Regulate AS160 Phosphorylation in Response to Insulin, AICAR, and Contraction in Mouse Skeletal Muscle

Henning F. Kramer1, Carol A. Witczak1, Nobuharu Fujii1, Niels Jessen1, Eric B. Taylor1, David E. Arnolds1, Kei Sakamoto1, Michael F. Hirshman1, and Laurie J. Goodyear1,2

1 Metabolism Research Division, Joslin Diabetes Center, Boston, Massachusetts
2 Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Laurie J. Goodyear, Section Head, Metabolism, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215. E-mail: laurie.goodyear{at}joslin.harvard.edu

Abbreviations: {alpha}2i, {alpha}2-inactive; AMPK, AMP-activated protein kinase; aPKC, atypical protein kinase C; AS160, Akt substrate of 160 kDa; EDL, extensor digitorum longus; GAP, GTPase-activating protein; PAS, phospho-Akt substrate; PI3-K, phosphatidylinositol 3-kinase

Insulin and contraction increase GLUT4 translocation in skeletal muscle via distinct signaling mechanisms. Akt substrate of 160 kDa (AS160) mediates insulin-stimulated GLUT4 translocation in L6 myotubes, presumably through activation of Akt. Using in vivo, in vitro, and in situ methods, insulin, contraction, and the AMP-activated protein kinase (AMPK) activator AICAR all increased AS160 phosphorylation in mouse skeletal muscle. Insulin-stimulated AS160 phosphorylation was fully blunted by wortmannin in vitro and in Akt2 knockout (KO) mice in vivo. In contrast, contraction-stimulated AS160 phosphorylation was only partially decreased by wortmannin and unaffected in Akt2 KO mice, suggesting additional regulatory mechanisms. To determine if AMPK mediates AS160 signaling, we used AMPK {alpha}2-inactive ({alpha}2i) transgenic mice. AICAR-stimulated AS160 phosphorylation was fully inhibited, whereas contraction-stimulated AS160 phosphorylation was partially reduced in the AMPK {alpha}2i transgenic mice. Combined AMPK {alpha}2 and Akt inhibition by wortmannin treatment of AMPK {alpha}2 transgenic mice did not fully ablate contraction-stimulated AS160 phosphorylation. Maximal insulin, together with either AICAR or contraction, increased AS160 phosphorylation in an additive manner. In conclusion, AS160 may be a point of convergence linking insulin, contraction, and AICAR signaling. While Akt and AMPK {alpha}2 activities are essential for AS160 phosphorylation by insulin and AICAR, respectively, neither kinase is indispensable for the entire effects of contraction on AS160 phosphorylation.


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