Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells

Deldicque, Louise; Canedo, Cossette Sanchez; Horman, Sandrine; Potter, I De; Bertrand, Luc; Hue, Louis; Francaux, Marc

doi:10.1007/s00726-007-0607-z

Cited by 55 publications

(51 citation statements)

References 25 publications

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“…However, a study by Averous et al (2014), reports that mTORC1 activity does not correlate with its lysosomal localization in serum-fed cells. Other mechanisms for glutamine regulation of mTORC1 have been proposed, including increasing the influx of leucine via the heterodimeric cotransporter SLC7A5-SLC3A2 (Nicklin et al 2009), increasing the levels of a-ketoglutarate (Yao et al 2012), and decreasing Akt activity (Deldicque et al 2008). The results of our biochemical evaluation of several pathways known to regulate mTOR did not reveal a clear candidate signaling pathway that was responsible for the observed effects.…”

Section: Discussionmentioning

confidence: 57%

“…mTORC1 is a critical cellular energy and nutrient status sensor that integrates signals from multiple pathways to regulate protein, lipid, and nucleotide synthesis, and it has also been identified as an important modulator of learning and memory (Dash et al 2006;Gkogkas et al 2010;Hoeffer and Klann 2010;Graber et al 2013;Santini et al 2014). Previous studies using cultured cells deprived of serum/amino acids have shown that glutamine can either increase or decrease mTORC1 activity (Deldicque et al 2008;Nicklin et al 2009;Kim et al 2013). However, as these in vitro studies were carried out under serumand/or amino acid-deprived culture conditions, the physiological relevance of these findings remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported that glutamine can inhibit mTORC1 activity in vitro using cultured cells deprived of serum and amino acids, a nonphysiological condition (Nakajo et al 2005;Deldicque et al 2008). We questioned if glutamine infused into the rat hippocampus can have similar effect in vivo, as assessed by phosphorylation of the known downstream targets ribosomal S6 kinase (S6K) and ribosomal protein S6 (S6).…”

Section: Glutamine Inhibits Mtorc1 Activity In Vivomentioning

confidence: 97%

“…It has been previously reported that leucine can enhance mTORC1 (Deldicque et al 2008;Dodd and Tee 2012;Suryawan et al 2012;Xu et al 2013). To examine if the mTORC1 inhibitory effect of glutamine can be neutralized by coadministration of leucine in vivo, independent groups of rats were infused with leucine (27 mg) targeted to one hippocampus while Glutamine impairs long-term memory www.learnmem.org an equal volume of vehicle was simultaneously infused into the contralateral hippocampus.…”

Section: Memory Impairing Effect Of Glutamine Can Be Overcome By Coadmentioning

confidence: 99%

“…However, other studies have demonstrated that glutamine can either inhibit (Nakajo et al 2005;Deldicque et al 2008) or stimulate (Nicklin et al 2009;Chiu et al 2012;Willems et al 2013) mTORC1 activity, although the mechanism(s) through which this is accomplished are not yet clear. Although these and other studies that have examined the influence of glutamine on mTORC1 activity using cells cultured in vitro, they were typically carried out using serum-and/or amino acid-free conditions to induce a state of starvation.…”

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confidence: 99%

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Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

et al. 2015

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The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum-and amino acidstarved cells have reported that glutamine addition can either stimulate or repress mTORC1 activity, depending on the particular experimental system that was used. However, these experiments do not directly address the effect of glutamine on mTORC1 activity under physiological conditions in nondeprived cells in vivo. We present experimental results indicating that intrahippocampal administration of glutamine to rats reduces mTORC1 activity. Moreover, post-training administration of glutamine impairs long-term spatial memory formation, while coadministration of glutamine with leucine had no influence on memory. Intracellular recordings in hippocampal slices showed that glutamine did not alter either excitatory or inhibitory synaptic activity, suggesting that the observed memory impairments may not result from conversion of glutamine to either glutamate or GABA. Taken together, these findings indicate that glutamine can decrease mTORC1 activity in the brain and may have implications for treatments of neurological diseases associated with high mTORC1 signaling.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Glutamine Inhibits Mtorc1 Activity In Vivomentioning

confidence: 97%

Section: Memory Impairing Effect Of Glutamine Can Be Overcome By Coadmentioning

confidence: 99%

mentioning

confidence: 99%

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Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

et al. 2015

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Negative effects of the amino acids Lys, His, and Thr on S6K1 phosphorylation in mammary epithelial cells

Prizant

Barash

2008

J of Cellular Biochemistry

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The role of essential amino acids (AA) on protein synthesis via the mTOR pathway was studied in murine mammary epithelial cells cultured under lactogenic conditions. Leu, Ile, and Val increased S6K1 phosphorylation compared to that measured in AA-deprived cells. Trp, Phe, and Met had no effect. Surprisingly, Lys, His, and Thr inhibited S6K1 phosphorylation in both murine and bovine mammary cells. Thr exhibited the most potent inhibition, being the only amino acid that competed with Leu's positive role. In non-deprived cells, there was no observable effect of Lys, His, or Thr on S6K1 phosphorylation at concentrations up to five times those in the medium. However, their addition as a mix revealed a synergistic negative effect. Supplementation of Lys, His, and Thr abrogated mTOR Ser 2448 phosphorylation, with no effect on Akt Ser 473-an mTORC2 target. This confirms specific mTORC1 regulation of S6K1 phosphorylation. The individual supplementation of Lys, His, and Thr maintained a low level of IRS-1 phosphorylation, which was dose-dependently increased by their combined addition. Thus, in parallel to inhibiting S6K1 activity, these AA may act synergistically to activate an additional kinase, phosphorylating IRS-1 via an S6K1-independent pathway. In cultures supplemented by Lys, His, and Thr, cellular protein synthesis decreased by up to 65%. A more pronounced effect was observed on beta-casein synthesis. These findings indicate that positive and negative signaling from AA to the mTOR pathway, combined with modulation of insulin sensitization, mediate the synthesis rates of total and specific milk proteins in mammary epithelial cells.

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Mechanical Stimulation and IGF‐1 Enhance mRNA Translation Rate in Osteoblasts Via Activation of the AKT‐mTOR Pathway

Bakker

Gakes

Hogervorst

et al. 2015

Journal Cellular Physiology

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Insulin-like growth factor-1 (IGF-1) is anabolic for muscle by enhancing the rate of mRNA translation via activation of AKT and subsequent activation of the mammalian target of rapamycin complex 1 (mTOR), thereby increasing cellular protein production. IGF-1 is also anabolic for bone, but whether the mTOR pathway plays a role in the rate of bone matrix protein production by osteoblasts is unknown. We hypothesized that anabolic stimuli such as mechanical loading and IGF-1 stimulate protein synthesis in osteoblasts via activation of the AKT-mTOR pathway. MC3T3-E1 osteoblasts were either or not subjected for 1 h to mechanical loading by pulsating fluid flow (PFF) or treated with or without human recombinant IGF-1 (1-100 ng/ml) for 0.5-6 h, to determine phosphorylation of AKT and p70S6K (downstream of mTOR) by Western blot. After 4 days of culture with or without the mTOR inhibitor rapamycin, total protein, DNA, and gene expression were quantified. IGF-1 (100 ng/ml) reduced IGF-1 gene expression, although PFF enhanced IGF-1 expression. IGF-1 did not affect collagen-I gene expression. IGF-1 dose-dependently enhanced AKT and p70S6K phosphorylation at 2 and 6 h. PFF enhanced phosphorylation of AKT and p70S6K already within 1 h. Both IGF-1 and PFF enhanced total protein per cell by ∼30%, but not in the presence of rapamycin. Our results show that IGF-1 and PFF activate mTOR, thereby stimulating the rate of mRNA translation in osteoblasts. The known anabolic effect of mechanical loading and IGF-1 on bone may thus be partly explained by mTOR-mediated enhanced protein synthesis in osteoblasts.

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Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells

Cited by 55 publications

References 25 publications

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

Negative effects of the amino acids Lys, His, and Thr on S6K1 phosphorylation in mammary epithelial cells

Mechanical Stimulation and IGF‐1 Enhance mRNA Translation Rate in Osteoblasts Via Activation of the AKT‐mTOR Pathway

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