IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Clin Exp Med 1(1),50-63;2008

Original Article
Sepsis and AMPK Activation by AICAR Differentially Regulate FoxO-1, -3 and -4
mRNA in Striated Muscle

Gerald J. Nystrom and Charles H. Lang

Department of Cellular & Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Received November 26, 2007; accepted January 10, 2008; available online January 20, 2008

Abstract: Although much is known regarding the posttranslational regulation of the FoxO transcription factors, there is little appreciation
of how stressors which regulate cellular energy status effect the various FoxO proteins at the mRNA level. The hypothesis of the
present study was that exposure of differentiated muscle cells to agonists of AMP-activated protein kinase (AMPK) would increase the
mRNA content of various FoxO mRNA transcripts. Stimulation of AMPK in vivo by the injection of AICAR into mice increased FoxO1 and
FoxO3 (but not FoxO4) mRNA in skeletal muscle. A comparable increase in these FoxO mRNAs was seen in skeletal muscle in
response to sepsis which also increased AMPK phosphorylation. In contradistinction to the in vivo data, FoxO1, 3 and 4 mRNA content
was decreased dose-dependently, with the decrement in FoxO1 being the largest, in C2C12 myocytes incubated with the AMPK
agonists AICAR or metformin. Treatment of myocytes with 2-deoxyglucose or reducing the media glucose concentration also
decreased mRNA content for FoxO1 and FoxO4. All stressors increased AMPK phosphorylation. Incubation of myocytes with AICAR
decreased the rate of protein synthesis and increased protein degradation. Finally, treatment with the AMPK inhibitor compound C
prevented both the AICAR-induced changes in FoxO mRNA and changes in protein metabolism. Our data indicate FoxO mRNA
expression is down-regulated by AMPK activation and energy depletion in cultured myocytes, but that a contrasting increase in FoxO1
and FoxO3 mRNA is observed in vivo with the agent and in response to sepsis suggesting the expression of these FoxOs is controlled
by other hormonal or energy sensing cues under in vivo conditions. . (IJCEM711001).

Key Words: sepsis; energy stress; protein synthesis; muscle

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Address all correspondence to: Charles H. Lang, PhD, Department of Cellular and Molecular Physiology, Pennsylvania State
University College of Medicine, 500 University Drive, Hershey, PA 17033, Phone : (717) 531 – 5346, Fax : (717) 531 – 7667, E-mail: