Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle

Henning F Kramer; Carol A Witczak; Nobuharu Fujii; Niels Jessen; Eric B Taylor; David E Arnolds; Kei Sakamoto; Michael F Hirshman; Laurie J Goodyear

doi:10.2337/db06-0150

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Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle

Journal article

Peer reviewed

Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle

Henning F Kramer, Carol A Witczak, Nobuharu Fujii, Niels Jessen, Eric B Taylor, David E Arnolds, Kei Sakamoto, Michael F Hirshman and Laurie J Goodyear

Diabetes (New York, N.Y.), Vol.55(7), pp.2067-2076

07/2006

DOI: 10.2337/db06-0150

PMID: 16804077

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Abstract

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 alpha2-inactive (alpha2i) transgenic mice. AICAR-stimulated AS160 phosphorylation was fully inhibited, whereas contraction-stimulated AS160 phosphorylation was partially reduced in the AMPK alpha2i transgenic mice. Combined AMPK alpha2 and Akt inhibition by wortmannin treatment of AMPK alpha2 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 alpha2 activities are essential for AS160 phosphorylation by insulin and AICAR, respectively, neither kinase is indispensable for the entire effects of contraction on AS160 phosphorylation.

Insulin - pharmacology

Phosphorylation

GTPase-Activating Proteins - drug effects

Glucose Transporter Type 4 - metabolism

Mice, Inbred C57BL

Male

GTPase-Activating Proteins - metabolism

Muscle, Skeletal - physiology

Aminoimidazole Carboxamide - pharmacology

Protein Transport

Ribonucleotides - pharmacology

Animals

Aminoimidazole Carboxamide - analogs & derivatives

Muscle Contraction - drug effects

Adenylate Kinase - metabolism

Muscle Contraction - physiology

Muscle, Skeletal - drug effects

Female

Signal Transduction - physiology

Mice

Kinetics

Details

Title: Subtitle: Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle
Creators: Henning F Kramer - Section Head, Metabolism, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215, USA
Carol A Witczak
Nobuharu Fujii
Niels Jessen
Eric B Taylor
David E Arnolds
Kei Sakamoto
Michael F Hirshman
Laurie J Goodyear
Resource Type: Journal article
Publication Details: Diabetes (New York, N.Y.), Vol.55(7), pp.2067-2076
Publisher: United States
DOI: 10.2337/db06-0150
PMID: 16804077
ISSN: 0012-1797
eISSN: 1939-327X
Grant note: AR45670 / NIAMS NIH HHS DK36836 / NIDDK NIH HHS F32 AR051663 / NIAMS NIH HHS AR42238 / NIAMS NIH HHS
Language: English
Date published: 07/2006
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984025330502771

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