| RRC ID |
45207
|
| 著者 |
Kamei Y, Hattori M, Hatazawa Y, Kasahara T, Kanou M, Kanai S, Yuan X, Suganami T, Lamers WH, Kitamura T, Ogawa Y.
|
| タイトル |
FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3'-UTR: possible contribution to ammonia detoxification.
|
| ジャーナル |
Am J Physiol Endocrinol Metab
|
| 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.
|
| 巻・号 |
307(6)
|
| ページ |
E485-93
|
| 公開日 |
2014-9-15
|
| DOI |
10.1152/ajpendo.00177.2014
|
| PII |
ajpendo.00177.2014
|
| PMID |
25074987
|
| MeSH |
3' Untranslated Regions / genetics
3' Untranslated Regions / physiology*
Amino Acids / metabolism
Ammonia / metabolism*
Ammonia / toxicity
Animals
Cell Line
Chromatin Immunoprecipitation
Forkhead Box Protein O1
Forkhead Transcription Factors / physiology*
Gene Expression Regulation / physiology
Glutamate-Ammonia Ligase / genetics*
Glutamate-Ammonia Ligase / physiology*
Glutamine / metabolism
Mice
Mice, Transgenic
Muscle, Skeletal / enzymology*
Plasmids / genetics
Real-Time Polymerase Chain Reaction
Transfection
|
| IF |
3.469
|
| 引用数 |
10
|
|
WOS 分野
|
PHYSIOLOGY
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
C2C12(RCB0987) |
