title: FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3'-UTR: possible contribution to ammonia detoxification.
abstract: Skeletal muscle is a reservoir of energy in the form of protein, which is degraded under catabolic conditions, resulting in the formation of amino acids and ammonia as a byproduct. The expression of FOXO1, a forkhead-type transcription factor, increases during starvation and exercise. In agreement, transgenic FOXO1-Tg mice that overexpress FOXO1 in skeletal muscle exhibit muscle atrophy. The aim of this study was to examine the role of FOXO1 in amino acid metabolism. The mRNA and protein expressions of glutamine synthetase (GS) were increased in skeletal muscle of FOXO1-Tg mice. Fasting induced FOXO1 and GS expression in wild-type mice but hardly increased GS expression in muscle-specific FOXO1 knockout (FOXO1-KO) mice. Activation of FOXO1 also increased GS mRNA and protein expression in C2C12 myoblasts. Using a transient transfection reporter assay, we observed that FOXO1 activated the GS reporter construct. Mutation of a putative FOXO1-binding consensus sequence in the downstream genomic region of GS decreased basal and FOXO1-dependent reporter activity significantly. A chromatin immunoprecipitation assay showed that FOXO1 was recruited to the 3' region of GS in C2C12 myoblasts. These results suggest that FOXO1 directly upregulates GS expression. GS is considered to mediate ammonia clearance in skeletal muscle. In agreement, an intravenous ammonia challenge increased blood ammonia concentrations to a twofold higher level in FOXO1-KO than in wild-type mice, demonstrating that the capacity for ammonia disposal correlated inversely with the expression of GS in muscle. These data indicate that FOXO1 plays a role in amino acid metabolism during protein degradation in skeletal muscle.
authors: Department of Organ Network and Metabolism and Laboratory of Molecular Nutrition, Graduate School of Environmental and Life Science, Kyoto Prefectural University, Kyoto, Japan; kamei@kpu.ac.jp.
authors: Yasutomi
authors: Y
authors: Kamei
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Maki
authors: M
authors: Hattori
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Laboratory of Molecular Nutrition, Graduate School of Environmental and Life Science, Kyoto Prefectural University, Kyoto, Japan;
authors: Yukino
authors: Y
authors: Hatazawa
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Tomomi
authors: T
authors: Kasahara
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Masanobu
authors: M
authors: Kanou
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Sayaka
authors: S
authors: Kanai
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Xunmei
authors: X
authors: Yuan
authors: Department of Organ Network and Metabolism and.
authors: Takayoshi
authors: T
authors: Suganami
authors: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors: Wouter H
authors: WH
authors: Lamers
authors: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors: Tadahiro
authors: T
authors: Kitamura
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
authors: Yoshihiro
authors: Y
authors: Ogawa
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000502:physiology*; D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D005974:Glutamate-Ammonia Ligase / Q000235:genetics* / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology*; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D000596:Amino Acids; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D005973:Glutamine; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase
keywords: 3′-untranslated region; amino acid; ammonia; forkhead box protein O1; gene regulation; skeletal muscle metabolism; transcription factors