FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3'-UTR: possible contribution to ammonia detoxification.

  title={FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3'-UTR: possible contribution to ammonia detoxification.},
  author={Yasutomi Kamei and Maki Hattori and Yukino Hatazawa and Tomomi Kasahara and Masanobu Kanou and Sayaka Kanai and Xunmei Yuan and Takayoshi Suganami and Wouter H. Lamers and Tadahiro Kitamura and Yoshihiro Ogawa},
  journal={American journal of physiology. Endocrinology and metabolism},
  volume={307 6},
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… 

Figures from this paper

Vitamin D Attenuates FOXO1-Target Atrophy Gene Expression in C2C12 Muscle Cells.

Vitamin D inhibited FOXO1-mediated transcriptional activity in a reporter gene assay and suppressed the glucocorticoid-induced gene expression of atrogin 1 and cathepsin L in C2C12 myoblasts, suggesting that vitamin D may prevent muscle atrophy via the FOXO 1-mediated pathway in muscle cells.

FOXO1 suppresses PGC‐1β gene expression in skeletal muscles

It is shown that PGC‐1β gene expression is negatively correlated with the expression of a transcription factor, forkhead box protein O1 (FOXO1), whose expression is increased during muscle atrophy, and that FOXO1 activation suppresses PGC-1β expression during atrophy.

Regulation of Skeletal Muscle Function by Amino Acids

β-alanine supplementation increased the physical performance and improved the executive function induced by endurance exercise in middle-aged individuals, and Oral 5-aminolevulinic acid supplementation can protect against mild hyperglycemia and help prevent type 2 diabetes.

Phosphorylation of 4EBP by oral leucine administration was suppressed in the skeletal muscle of PGC-1α knockout mice

Data suggest that skeletal muscle-PGC-1α is important for leucine-mediated mTOR activation and protein biosynthesis, and attenuated 4EBP phosphorylation in the skeletal muscle, but not in the liver, of the PGC-1 α knockout mice.

Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties

It is demonstrated that impaired Gln-dependent nucleotide synthesis promotes FOXP3hi cells with regulator properties, and it remains to be investigated to what extent the concomitant retention of IL-17A–producing CD4 T cells may limit the therapeutic potential of Tregs enriched through targeting these pathways in vivo.

Mechanism of Gene Regulation in Skeletal Muscle Function

  • Y. Kamei
  • Biology, Medicine
    Nippon Eiyo Shokuryo Gakkaishi
  • 2022
This work has been investigating the role of a transcription factor, FOXO 1, which plays important roles in exercise, energy expenditure and glucose/amino acid metabolism, and glucose uptake in skeletal muscle.

FoxO transcription factors in cancer metabolism.

Assessment of a western blot signal for the Bcnt/Cfdp1, a tentative component of Srcap chromatin remodeling complex; trial to overcome off-target problems

Western blot with these validated antibodies indicated a preferential expression of Bcnt/Cfdp1 in the early stages of brain development in mouse and rat, which is consistent with the expression of Higgs boson-like motif in the BCNT-C domain.

Insertion/deletions within the bovine FoxO1 gene and their association analysis with growth traits in three Chinese cattle breeds.

The results suggested that these two Indels within the bovine FoxO1 gene might be used as genetic markers for marker-assisted selection (MAS) in cattle breeding and genetics.



Overexpression of FOXO1 in skeletal muscle does not alter longevity in mice

Skeletal Muscle FOXO1 (FKHR) Transgenic Mice Have Less Skeletal Muscle Mass, Down-regulated Type I (Slow Twitch/Red Muscle) Fiber Genes, and Impaired Glycemic Control*[boxs]

It is suggested that FOXO1 negatively regulates skeletal muscle mass and type I fiber gene expression and leads to impaired skeletal muscle function.

PGC-1α-Mediated Branched-Chain Amino Acid Metabolism in the Skeletal Muscle

In this study, microarray analysis revealed that the BCAA catabolic pathway was co‐ordinately activated in the skeletal muscles of transgenic mice overexpressing PGC‐1α, suggesting the activation of muscle BCAA metabolism by PGC•1α.

The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene.

Transient transfection assays demonstrate that the MuRF1 promoter is responsive to both the dexamethasone (DEX)-activated glucocorticoid receptor (GR) and FOXO1, whereas coexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter gene activity, presenting new insights into the role of the GR andFOXO family of transcription factors in the transcriptional regulation of the Mu RF1 gene.

Modulation of glutamine metabolism by the PI(3)K–PKB–FOXO network regulates autophagy

A growth-factor-responsive network that can directly modulate autophagy through the regulation of glutamine metabolism is revealed, suggesting that the induction ofautophagy by FOXO3-mediated glutamine synthetase expression is important for cellular survival.

Glutamine directly downregulates glutamine synthetase protein levels in mouse C2C12 skeletal muscle myotubes.

In mouse C2C12 skeletal muscle cells, glutamine synthetase protein expression is regulated by glutamine through changes in the rate of degradation of the protein, which is specific to glutamine, which acts directly without requiring prior metabolism.

Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification*

It is demonstrated that GS in muscle is dispensable in fed mice but plays a key role in mounting the adaptive response to fasting by transiently facilitating the production of glutamine and muscle GS contributes to ammonia detoxification and urea synthesis.