Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle

Greiwe, Jeffrey S.; Kwon, Guim; McDaniel, Michael L.; Semenkovich, Clay F.

doi:10.1152/ajpendo.2001.281.3.e466

Cited by 121 publications

(108 citation statements)

References 38 publications

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“…S6k activity through different pathways (9). In a recent study (2), a combination of insulin and amino acids was required to stimulate protein synthesis and inhibit protein degradation.…”

Section: Discussionmentioning

confidence: 99%

Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise

Karlsson

Nilsson²,

Nilsson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

223

216

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The aim of the study was to investigate the effect of resistance exercise alone or in combination with oral intake of branched-chain amino acids (BCAA) on phosphorylation of the 70-kDa S6 protein kinase (p70S6k) and mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and p38 MAPK in skeletal muscle. Seven male subjects performed one session of quadriceps muscle resistance training (4 × 10 repetitions at 80% of one repetition maximum) on two occasions. In a randomized order, double-blind, crossover test, subjects ingested a solution of BCAA or placebo during and after exercise. Ingestion of BCAA increased plasma concentrations of isoleucine, leucine, and valine during exercise and throughout recovery after exercise (2 h postexercise), whereas no change was noted after the placebo trial. Resistance exercise led to a robust increase in p70S6k phosphorylation at Ser424 and/or Thr421, which persisted 1 and 2 h after exercise. BCAA ingestion further enhanced p70S6k phosphorylation 3.5-fold during recovery. p70S6k phosphorylation at Thr389 was unaltered directly after resistance exercise. However, during recovery, Thr389 phosphorylation was profoundly increased, but only during the BCAA trial. Furthermore, phosphorylation of the ribosomal protein S6 was also increased in the recovery period only during the BCAA trial. Exercise led to a marked increase in ERK1/2 and p38 MAPK phosphorylation, which was completely suppressed upon recovery and unaltered by BCAA. In conclusion, BCAA, ingested during and after resistance exercise, mediate signal transduction through p70S6k in skeletal muscle.

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“…S6k activity through different pathways (9). In a recent study (2), a combination of insulin and amino acids was required to stimulate protein synthesis and inhibit protein degradation.…”

Section: Discussionmentioning

confidence: 99%

Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise

Karlsson

Nilsson²,

Nilsson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

223

216

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“…Indicators of mTOR signaling in these studies have been the phosphorylation of the two regulatory proteins p70 s6k and PHAS-I in a rapamycin-dependent manner. In an attempt to expand these findings to an in vivo setting, we have recently determined in collaboration with Clay Semenkovich at Washington University whether insulin and leucine can activate p70 s6k through these pathways in human skeletal muscle biopsies (46). To assess whether insulin and leucine mediate these effects by different pathways, we also monitored the phosphorylated form of Akt, an immediate upstream signaling component in the insulin signaling pathway.…”

Section: Evidence For Insulin and Nutrient Signaling In Vivomentioning

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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“…Leucine and IGF-I also phosphorylate and activate the Ser/Thr protein kinase S6K1 (14,22,47) and its physiologically relevant substrate, the ribosomal protein (rp)S6 (23,24). Although the proximal elements of the canonical signaling pathways differ for nutrients and growth factors, these anabolic stimuli do apparently share common distal signaling intermediates (12,14,19,20). Hence, it is unclear whether elevated FFA concentrations will have similar or differential effects on growth factor-and leucine-stimulated protein synthesis.…”

mentioning

confidence: 99%

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Lang¹

2006

American Journal of Physiology-Endocrinology and Metabolism

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Lang, Charles H. Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle. Am J Physiol Endocrinol Metab 291: E666 -E674, 2006. First published May 9, 2006; doi:10.1152/ajpendo.00065.2006.-Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ϳ25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E ⅐ eIF4G complex to the inactive eIF4E ⅐ 4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser 307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle. leucine; insulin-like growth factor I; eukaryotic initiation factor 4E-binding protein-1; eukaryotic initiation factor 4G; mammalian target of rapamycin; tuberous sclerosis complex 2 IN CONTRAST TO THE EXTENSIVE LITERATURE on the relationship between circulating free fatty acids (FFAs) and glucose metabolism, there is a paucity of information pertaining to the impact of FFAs on protein metabolism. Early studies where plasma FFAs were acutely increased by infusion of Intralipid plus heparin (9) reported a generalized hypoaminoacidemia. This response demonstrates a mismatch between the rates of appearance and disappearance of amino acids and suggests that elevated plasma FFAs increase protein synthesis and/or decrease proteolysis. This protein-sparing effect of lipid was confirmed in isotope dilution studies where radiolabeled leucine was used, which concluded that increased FFA availability was inversely related to the rate of whole body proteolysis (e.g., decreased rate of leucine appearance) b...

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Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle

Cited by 121 publications

References 38 publications

Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise

Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise

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

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

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Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle

Cited by 121 publications

References 38 publications

Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise

Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise

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

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

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Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise

Branched-chain amino acids increase p70^S6k phosphorylation in human skeletal muscle after resistance exercise