FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3'-UTR: possible contribution to ammonia detoxification
| Autor: | Yoshihiro Ogawa, Masanobu Kanou, Tomomi Kasahara, Tadahiro Kitamura, Maki Hattori, Yukino Hatazawa, Wouter H. Lamers, Xunmei Yuan, Yasutomi Kamei, Takayoshi Suganami, Sayaka Kanai |
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| Přispěvatelé: | Tytgat Institute for Liver and Intestinal Research |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Chromatin Immunoprecipitation
endocrine system Physiology Endocrinology Diabetes and Metabolism Glutamine FOXO1 Mice Transgenic Biology Real-Time Polymerase Chain Reaction Transfection digestive system Cell Line Ammonia chemistry.chemical_compound Mice Glutamate-Ammonia Ligase Physiology (medical) medicine Animals Amino Acids Muscle Skeletal Transcription factor 3' Untranslated Regions Regulation of gene expression chemistry.chemical_classification Three prime untranslated region Catabolism Forkhead Box Protein O1 Skeletal muscle nutritional and metabolic diseases food and beverages Forkhead Transcription Factors Amino acid medicine.anatomical_structure chemistry Biochemistry Gene Expression Regulation hormones hormone substitutes and hormone antagonists Plasmids |
| Zdroj: | American journal of physiology. Endocrinology and metabolism, 307(6), E485-E493. American Physiological Society |
| ISSN: | 0193-1849 |
| DOI: | 10.1152/ajpendo.00177.2014 |
| Popis: | 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 C2C12myoblasts. 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 C2C12myoblasts. 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. |
| Databáze: | OpenAIRE |
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