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J. Biol. Chem., Vol. 279, Issue 35, 36553-36561, August 27, 2004

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Preservation of Liver Protein Synthesis during Dietary Leucine Deprivation Occurs at the Expense of Skeletal Muscle Mass in Mice Deleted for eIF2 Kinase GCN2^*

Tracy G. Anthony, Brent J. McDaniel, Rachel L. Byerley, Barbara C. McGrath¶, Douglas R. Cavener¶, Margaret A. McNurlan||, and Ronald C. Wek**

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Evansville, Indiana 47712, the ^¶Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, the ^||Department of Surgery, State University of New York, Stony Brook, New York 11794, and the ^**Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

In eukaryotic cells, amino acid depletion reduces translation by a mechanism involving phosphorylation of eukaryotic initiation factor-2 (eIF2). Herein we describe that mice lacking the eIF2 kinase, general control nonderepressible 2 (GCN2) fail to alter the phosphorylation of this initiation factor in liver, and are moribund in response to dietary leucine restriction. Wild-type (GCN2^+/+) and two strains of GCN2 null (GCN2^–/–) mice were provided a nutritionally complete diet or a diet devoid of leucine or glycine for 1 h or 6 days. In wild-type mice, dietary leucine restriction resulted in loss of body weight and liver mass, yet mice remained healthy. In contrast, a significant proportion of GCN2^–/– mice died within 6 days of the leucine-deficient diet. Protein synthesis in wild-type livers was decreased concomitant with increased phosphorylation of eIF2 and decreased phosphorylation of 4E-BP1 and S6K1, translation regulators controlled nutritionally by mammalian target of rapamycin. Whereas translation in the liver was decreased independent of GCN2 activity in mice fed a leucine-free diet for 1 h, protein synthesis in GCN2^–/– mice at day 6 was enhanced to levels measured in mice fed the complete diet. Interestingly, in addition to a block in eIF2 phosphorylation, phosphorylation of 4E-BP1 and S6K1 was not decreased in GCN2^–/– mice deprived of leucine for 6 days. This suggests that GCN2 activity can also contribute to nutritional regulation of the mammalian target of rapamycin pathway. As a result of the absence of these translation inhibitory signals, liver weights were preserved and instead, skeletal muscle mass was reduced in GCN2^–/– mice fed a leucine-free diet. This study indicates that loss of GCN2 eIF2 kinase activity shifts the normal maintenance of protein mass away from skeletal muscle to provide substrate for continued hepatic translation.

Received for publication, April 26, 2004 , and in revised form, June 4, 2004.

^* This work was supported by National Institutes of Health Grants R01GM49164 (to R. C. W.) and R01AG17446 (to M. A. M.) and a grant from the Indiana University Purdue University Indianapolis Office for Professional Development (to T. G. A.). 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. Tel.: 812-465-1199; Fax: 812-465-1184; E-mail: tganthon{at}iupui.edu.

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