Stimulation of In Vitro Rat Muscle Protein Synthesis by Leucine Decreases with Age

Dardevet, Dominique; Sornet, Claire; Balage, Michèle; Grizard, Jean

doi:10.1093/jn/130.11.2630

Cited by 210 publications

(179 citation statements)

References 28 publications

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“…Furthermore, muscle mass in both humans and rodents decreases with age. In two studies using aging rats, Dardevet et al (49,50) have shown that the sensitivity of muscle protein synthesis to leucine stimulation was decreased and that this response could be restored by feeding a leucine-supplemented meal. Proposed model for coupling metabolically linked Krebs cycle fluxes in the ␤-cell mitochondria.…”

Section: Regulation Of Mtor By ␤-Cellsmentioning

confidence: 99%

Metabolic and Autocrine Regulation of the Mammalian Target of Rapamycin by Pancreatic β-Cells

et al. 2002

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Mammalian target of rapamycin (mTOR) is a serine and threonine protein kinase that regulates numerous cellular functions, in particular, the initiation of protein translation. mTOR-mediated phosphorylation of both the translational repressor eukaryotic initiation factor 4E binding protein-1 and p70 S6 kinase are early events that control the translation initiation process. Rapamycin, an inhibitor of mTOR, is a potent immunosuppressant due, in part, to its ability to interfere with T-cell activation at the level of translation, and it has gained a prominent role in preventing the development and progression of rejection in pancreatic islet transplant recipients. The characterization of the insulin signaling cascade that modulates mTOR in insulin-sensitive tissues has been a major focus of investigation. Recently, the ability of nutrients, in particular the branched-chain amino acid leucine, to activate mTOR independent of insulin by a process designated as nutrient signaling has been identified. The ␤-cell expresses components of the insulin signaling cascade and utilizes the metabolism of nutrients to affect insulin secretion. These combined transduction processes make the ␤-cell an unique cell to study metabolic and autocrine regulation of mTOR signaling. Our studies have described the ability of insulin and IGFs in concert with the nutrients leucine, glutamine, and glucose to modulate protein translation through mTOR in ␤-cells. These findings suggest that mitochondria-derived factors, ATP in particular, may be responsible for nutrient signaling. The significance of these findings is that the optimization of mitochondrial function is not only important for insulin secretion but may significantly impact the growth and proliferation of ␤-cells through these mTOR signaling pathways. Diabetes 51:2877-2885, 2002

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Section: Regulation Of Mtor By ␤-Cellsmentioning

confidence: 99%

Metabolic and Autocrine Regulation of the Mammalian Target of Rapamycin by Pancreatic β-Cells

et al. 2002

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“…EGF is a well described growth factor having tumor promoting action (45). TPA and EGF were reported to activate p90 RSK via phosphorylation (16,17,39,40) and were used here as positive controls for comparison with UVA for stimulation of p90 RSK phosphorylation. Our results show that like TPA and EGF, UVA induced phosphorylation of p90 RSK (Fig.…”

Section: Phosphorylation Of P90mentioning

confidence: 99%

“…However, p90 RSK phosphorylation shows the total levels of the homologous phosphorylated sites of RSK1, RSK2, and RSK3. Assay for p90 RSK Activity-p90 RSK activity was measured by an immune complex kinase assay using an S6 peptide AKRRRLSSLRA as a substrate according to the procedure recommended in the S6 kinase assay kit (Upstate Biotechnology, Inc.) (38,39). Briefly, cell lysates were prepared from JB6 Cl 41 cells or JB6 Cl 41 cells with DNM-JNK1, DNM-p38, or DNM-ERK2 grown in 100-mm dishes.…”

mentioning

confidence: 99%

UVA Induces Ser381 Phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK Pathways

Zhang

Zhong

Dong³

et al. 2001

Journal of Biological Chemistry

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“…Amino acid refeeding after short-term starvation increases muscle protein synthesis, and physiologically-relevant concentrations of amino acids enhance synthesis in the perfused hindlimb, in incubated muscle, and cultured myocytes (2)(3)(4)(5)(6)(7)(8). The branched-chain amino acid leucine accounts for all or most of the ability of a mixture of amino acids to stimulate protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…The branched-chain amino acid leucine accounts for all or most of the ability of a mixture of amino acids to stimulate protein synthesis. Moreover, the anabolic effects of leucine are mediated by cell signaling pathways which stimulate translation initiation via activation of mammalian target of rapamycin (mTOR) (2)(3)(4)(5)(6)(7)(8)(9)(10). This protein kinase represents a point of signal amplification because stimulation of mTOR phosphorylates multiple substrates which enhance translation, including eukaryotic initiation factor 4E-binding protein (4E-BP1) and the ribosomal protein (rp) S6 kinase-1(S6K1) (11).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Lang

Frost

2006

Mol Med

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Sepsis blunts the ability of nutrient signaling by leucine to stimulate skeletal muscle protein synthesis by impairing translation initiation. The present study tested the hypothesis that overproduction of either tumor necrosis factor (TNF)-α or glucocorticoids mediate the sepsis-induced leucine resistance. Prior to producing peritonitis, rats received either vehicle, TNF binding protein (TNF BP ) to inhibit endogenous TNFα action, and/or the glucocorticoid receptor antagonist RU486. Leucine was orally administered to all rats 24 h thereafter and the gastrocnemius removed 20 min later to assess protein synthesis and signaling components important in controlling peptide-chain initiation. Muscle protein synthesis was 65% lower in septic rats administered leucine than in leucinetreated control animals. This reduction was not prevented by either TNF BP or RU486 alone, but was completely reversed by the combination. This sepsis-induced leucine resistance was associated with an 80% reduction in the amount of active eIF4E·eIF4G complex, a 5-fold increase in the formation of the inactive eIF4E·4E-BP1 complex as well as markedly reduced (at least 70%) phosphorylation of 4E-BP1, eIF4G, S6K1, S6, and mTOR. Pretreatment of septic rats with either TNF BP or RU486 individually only nominally improved the leucine action as assessed by the above-mentioned endpoints. In contrast, when TNF BP and RU486 were co-administered, the ability of sepsis to impair the leucine-stimulated phosphorylation of 4E-BP1, eIF4G, S6K1, and S6 as well as the redistribution of eIF4E was essentially prevented. No differences in the total amount or phosphorylation of eIF2α and eIF2Bε were detected between the different groups, and changes could not be attributed to differences in the prevailing plasma concentration of insulin or leucine. Our data demonstrate the sepsis-induced leucine resistance in skeletal muscle results from the cooperative interaction of both TNFα and glucocorticoids.

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Stimulation of In Vitro Rat Muscle Protein Synthesis by Leucine Decreases with Age

Cited by 210 publications

References 28 publications

Metabolic and Autocrine Regulation of the Mammalian Target of Rapamycin by Pancreatic β-Cells

Metabolic and Autocrine Regulation of the Mammalian Target of Rapamycin by Pancreatic β-Cells

UVA Induces Ser381 Phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK Pathways

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

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