Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle

2004 ◽  
Vol 287 (2) ◽  
pp. E275-E281 ◽  
Author(s):  
Zhenqi Liu ◽  
Guolian Li ◽  
Scot R. Kimball ◽  
Linda A. Jahn ◽  
Eugene J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Translation Initiation ◽  
Human Skeletal Muscle ◽  
Mrna Translation ◽  
Nucleotide Exchange ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Guanine Nucleotide Exchange

Amino acids are unique anabolic agents in that they nutritively signal to mRNA translation initiation and serve as substrates for protein synthesis in skeletal muscle. Glucocorticoid excess antagonizes the anabolic action of amino acids on protein synthesis in laboratory animals. To examine whether excessive glucocorticoids modulate mixed amino acid-signaled translation initiation in human skeletal muscle, we infused an amino acid mixture (10% Travasol) systemically to 16 young healthy male volunteers for 6 h in the absence ( n = 8) or presence ( n = 8) of glucocorticoid excess (dexamethasone 2 mg orally every 6 h for 3 days). Vastus lateralis muscles were biopsied before and after amino acid infusion, and the phosphorylation of eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1), ribosomal protein S6 kinase (p70S6K), and eIF2α and the guanine nucleotide exchange activity of eIF2B were measured. Systemic infusion of mixed amino acids significantly stimulated the phosphorylation of 4E-BP1 ( P < 0.04) and p70S6K ( P < 0.001) and the dephosphorylation of eIF2α ( P < 0.003) in the control group. Dexamethasone treatment did not alter the basal phosphorylation state of 4E-BP1, p70S6K, or eIF2α; however, it abrogated the stimulatory effect of amino acid infusion on the phosphorylation of 4E-BP1 ( P = 0.31) without affecting amino acid-induced phosphorylation of p70S6K ( P = 0.002) or dephosphorylation of eIF2α ( P = 0.003). Neither amino acid nor dexamethasone treatment altered the guanine nucleotide exchange activity of eIF2B. We conclude that changes of amino acid concentrations within the physiological range stimulate mRNA translation by enhancing the binding of mRNA to the 43S preinitiation complex, and the activity of p70S6K and glucocorticoid excess blocks the former action in vivo in human skeletal muscle.

scholarly journals Insulin is required for amino acid stimulation of dual pathways for translational control in skeletal muscle in the late-gestation ovine fetus

2009 ◽  
Vol 296 (1) ◽  
pp. E56-E63 ◽  
Author(s):  
Laura D. Brown ◽  
Paul J. Rozance ◽  
James S. Barry ◽  
Jacob E. Friedman ◽  
William W. Hay
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Ribosomal Protein ◽  
Translation Initiation ◽  
Late Gestation ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Ribosomal Protein S6 ◽  
Ovine Fetus

During late gestation, amino acids and insulin promote skeletal muscle protein synthesis. However, the independent effects of amino acids and insulin on the regulation of mRNA translation initiation in the fetus are relatively unknown. The purpose of this study was to determine whether acute amino acid infusion in the late-gestation ovine fetus, with and without a simultaneous increase in fetal insulin concentration, activates translation initiation pathway(s) in skeletal muscle. Fetuses received saline (C), mixed amino acid infusion plus somatostatin infusion to suppress amino acid-stimulated fetal insulin secretion (AA+S), mixed amino acid infusion with concomitant physiological increase in fetal insulin (AA), or high-dose insulin infusion with euglycemia and euaminoacidemia (HI). After a 2-h infusion period, fetal skeletal muscle was harvested under in vivo steady-state conditions and frozen for quantification of proteins both upstream and downstream of mammalian target of rapamycin (mTOR). In the AA group, we found a threefold increase in ribosomal protein S6 kinase (p70S6k) and Erk1/2 phosphorylation; however, blocking the physiological rise in insulin with somatostatin in the AA+S group prevented this increase. In the HI group, Akt, Erk1/2, p70S6k, and ribosomal protein S6 were highly phosphorylated and 4E-binding protein 1 (4E-BP1) associated with eukaryotic initiation factor (eIF)4E decreased by 30%. These data show that insulin is a significant regulator of intermediates involved in translation initiation in ovine fetal skeletal muscle. Furthermore, the effect of amino acids is dependent on a concomitant increase in fetal insulin concentrations, because amino acid infusion upregulates p70S6k and Erk only when amino acid-stimulated increase in insulin occurs.

Invited Review: Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise

2002 ◽  
Vol 93 (3) ◽  
pp. 1168-1180 ◽  
Author(s):  
Scot R. Kimball ◽  
Peter A. Farrell ◽  
Leonard S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Translation Initiation ◽  
Translational Control ◽  
Initiation Factor ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Amino Acid Availability

Protein synthesis in skeletal muscle is modulated in response to a variety of stimuli. Two stimuli receiving a great deal of recent attention are increased amino acid availability and exercise. Both of these effectors stimulate protein synthesis in part through activation of translation initiation. However, the full response of translation initiation and protein synthesis to either effector is not observed in the absence of a minimal concentration of insulin. The combination of insulin and either increased amino acid availability or endurance exercise stimulates translation initiation and protein synthesis in part through activation of the ribosomal protein S6 protein kinase S6K1 as well as through enhanced association of eukaryotic initiation factor eIF4G with eIF4E, an event that promotes binding of mRNA to the ribosome. In contrast, insulin in combination with resistance exercise stimulates translation initiation and protein synthesis through enhanced activity of a guanine nucleotide exchange protein referred to as eIF2B. In both cases, the amount of insulin required for the effects is low, and a concentration of the hormone that approximates that observed in fasting animals is sufficient for maximal stimulation. This review summarizes the results of a number of recent studies that have helped to establish our present understanding of the interactions of insulin, amino acids, and exercise in the regulation of protein synthesis in skeletal muscle.

Removal of infused amino acids by splanchnic and leg tissues in humans

1986 ◽  
Vol 250 (4) ◽  
pp. E407-E413 ◽  
Author(s):  
R. A. Gelfand ◽  
M. G. Glickman ◽  
R. Jacob ◽  
R. S. Sherwin ◽  
R. A. DeFronzo
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Uptake ◽  
Branched Chain Amino Acids ◽  
Acid Uptake ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Significant Uptake ◽  
Branched Chain

To compare the contributions of splanchnic and skeletal muscle tissues to the disposal of intravenously administered amino acids, regional amino acid exchange was measured across the splanchnic bed and leg in 11 normal volunteers. Postabsorptively, net release of amino acids by leg (largely alanine and glutamine) was complemented by the net splanchnic uptake of amino acids. Amino acid infusion via peripheral vein (0.2 g X kg-1 X h-1) caused a doubling of plasma insulin and glucagon levels and a threefold rise in blood amino acid concentrations. Both splanchnic and leg tissues showed significant uptake of infused amino acids. Splanchnic tissues accounted for approximately 70% of the total body amino acid nitrogen disposal; splanchnic uptake was greatest for the glucogenic amino acids but also included significant quantities of branched-chain amino acids. In contrast, leg amino acid uptake was dominated by the branched-chain amino acids. Based on the measured leg balance, body skeletal muscle was estimated to remove approximately 25-30% of the total infused amino acid load and approximately 65-70% of the infused branched-chain amino acids. Amino acid infusion significantly stimulated both the leg efflux and the splanchnic uptake of glutamine (not contained in the infusate). We conclude that when amino acids are infused peripherally in normal humans, splanchnic viscera (liver and gut) are the major sites of amino acid disposal.

Response of rat heart and skeletal muscle protein in vivo to insulin and amino acid infusion

1993 ◽  
Vol 264 (6) ◽  
pp. E958-E965 ◽  
Author(s):  
P. H. McNulty ◽  
L. H. Young ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Acid Infusion ◽  
Amino Acid Infusion

Whether insulin, at physiological concentrations, stimulates net muscle protein synthesis in vivo remains unresolved. To examine this, we infused either saline, insulin (2.8 mU.kg-1.min-1, euglycemic clamp), an amino acid solution, or insulin plus amino acids for 4 h into awake overnight-fasted rats. Heart and skeletal muscle protein synthesis was measured by either a continuous tracer infusion method, using L-[1-14C]leucine, L-[2,5-3H]leucine, or L-[ring-2,6-3H]phenylalanine or by injection of L-[ring-2,6-3H]phenylalanine with a pool-flooding bolus of unlabeled phenylalanine. In heart, synthesis rates obtained using the arterial plasma specific activity of [3H]phenylalanine administered as either a tracer infusion or flooding bolus were comparable in saline-treated rats (range 10.9 +/- 1.2 to 12.2 +/- 0.9%/day) and were not affected by infusion of insulin or amino acids. Estimates using continuous infusion of L-[1-14C]leucine were significantly lower (P < 0.001), except when unlabeled amino acids were given also. In skeletal muscle, rates estimated using the flooding bolus (6.7 +/- 0.8%/day) were also not affected by insulin or amino acids. Estimates using continuous infusion of [3H]leucine (2.6 +/- 0.3%/day) or [3H]phenylalanine (2.8 +/- 1.0%/day) were lower and were still lower using [14C]leucine (1.6 +/- 0.6%/day), but increased toward those estimated with the flooding bolus during amino acid infusion. We conclude that, in heart muscle of the mature rat in vivo, neither insulin nor amino acids affect protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino acids regulate skeletal muscle PHAS-I and p70 S6-kinase phosphorylation independently of insulin

2000 ◽  
Vol 279 (2) ◽  
pp. E301-E306 ◽  
Author(s):  
W. Long ◽  
L. Saffer ◽  
L. Wei ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Rat Skeletal Muscle ◽  
S6 Kinase ◽  
Acid Infusion ◽  
P70 S6 Kinase ◽  
Amino Acid Infusion

Refeeding reverses the muscle protein loss seen with fasting. The physiological regulators and cellular control sites responsible for this reversal are incompletely defined. Phosphorylation of phosphorylated heat-acid stabled protein (PHAS-I) frees eukaryotic initiation factor 4E (eIF4E) and stimulates protein synthesis by accelerating translation initiation. Phosphorylation of p70 S6-kinase (p70S6k) is thought to be involved in the regulation of the synthesis of some ribosomsal proteins and other selected proteins with polypyrimidine clusters near the transcription start site. We examined whether phosphorylation of PHAS-I and p70S6k was increased by feeding and determined the separate effects of insulin and amino acids on PHAS-I and p70S6k phosphorylation in rat skeletal muscle in vivo. Muscle was obtained from rats fed ad libitum or fasted overnight ( n = 5 each). Other fasted rats were infused with insulin (3 μU · min−1 · kg−1, euglycemic clamp), amino acids, or the two combined. Gastrocnemius was freeze-clamped, and PHAS-I and p70S6k phosphorylation was measured by quantifying the several phosphorylated forms of these proteins seen on Western blots. We observed that feeding increased phosphorylation of both PHAS-I and p70S6k ( P < 0.05). Infusion of amino acids alone reproduced the effect of feeding. Physiological hyperinsulinemia increased p70S6K ( P< 0.05) but not PHAS-I phosphorylation ( P = 0.98). Addition of insulin to amino acid infusion was no more effective than amino acids alone in promoting PHAS-I and p70S6kphosphorylation. We conclude that amino acid infusion alone enhances the activation of the protein synthetic pathways in vivo in rat skeletal muscle. This effect is not dependent on increases in plasma insulin and simulates the activation of protein synthesis that accompanies normal feeding.

scholarly journals Skeletal Muscle Is Anabolically Unresponsive to an Amino Acid Infusion in Pediatric Burn Patients 6 Months Postinjury

2011 ◽  
Vol 253 (3) ◽  
pp. 592-597 ◽  
Author(s):  
Demidmaa Tuvdendorj ◽  
David L. Chinkes ◽  
Xiao-Jun Zhang ◽  
Melinda Sheffield-Moore ◽  
David N. Herndon
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Burn Patients ◽  
Acid Infusion ◽  
Amino Acid Infusion

scholarly journals Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids

1988 ◽  
Vol 254 (2) ◽  
pp. 579-584 ◽  
Author(s):  
P J Garlick ◽  
I Grant
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Branched Chain Amino Acids ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Branched Chain

Rates of muscle protein synthesis were measured in vivo in tissues of post-absorptive young rats that were given intravenous infusions of various combinations of insulin and amino acids. In the absence of amino acid infusion, there was a steady rise in muscle protein synthesis with plasma insulin concentration up to 158 mu units/ml, but when a complete amino acids mixtures was included maximal rates were obtained at 20 mu units/ml. The effect of the complete mixture could be reproduced by a mixture of essential amino acids or of branched-chain amino acids, but not by a non-essential mixture, alanine, methionine or glutamine. It is concluded that amino acids, particularly the branched-chain ones, increase the sensitivity of muscle protein synthesis to insulin.

Combined effects of hyperaminoacidemia and oxandrolone on skeletal muscle protein synthesis

2000 ◽  
Vol 278 (2) ◽  
pp. E273-E279 ◽  
Author(s):  
Melinda Sheffield-Moore ◽  
Robert R. Wolfe ◽  
Dennis C. Gore ◽  
Steven E. Wolf ◽  
Dennis M. Ferrer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Compartment Model ◽  
Acid Mixture ◽  
Skeletal Muscle Protein ◽  
Amino Acid Infusion

We investigated whether the normal anabolic effects of acute hyperaminoacidemia were maintained after 5 days of oxandrolone (Oxandrin, Ox)-induced anabolism. Five healthy men [22 ± 3 (SD) yr] were studied before and after 5 days of oral Ox (15 mg/day). In each study, a 5-h basal period was followed by a 3-h primed-continuous infusion of a commercial amino acid mixture (10% Travasol). Stable isotopic data from blood and muscle sampling were analyzed using a three-compartment model to calculate muscle protein synthesis and breakdown. Model-derived muscle protein synthesis increased after amino acid infusion in both the control [basal control (BC) vs. control + amino acids (C+AA); P < 0.001] and Ox study [basal Ox (BOx) vs. Ox + amino acids (Ox+AA); P < 0.01], whereas protein breakdown was unchanged. Fractional synthetic rates of muscle protein increased 94% (BC vs. C+AA; P = 0.01) and 53% (BOx vs. Ox+AA; P < 0.01), respectively. We conclude that the normal anabolic effects of acute hyperaminoacidemia are maintained in skeletal muscle undergoing oxandrolone-induced anabolism.

Effects of flooding amino acids on incorporation of labeled amino acids into human muscle protein

1998 ◽  
Vol 275 (1) ◽  
pp. E73-E78 ◽  
Author(s):  
Kenneth Smith ◽  
Nigel Reynolds ◽  
Shaun Downie ◽  
Ayyub Patel ◽  
Michael J. Rennie
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Large Dose ◽  
Human Skeletal Muscle ◽  
Muscle Protein ◽  
Human Muscle ◽  
Leucine Incorporation ◽  
Nonessential Amino Acids ◽  
Stimulation Of

We investigated the effects of the nature of the flooding amino acid on the rate of incorporation of tracer leucine into human skeletal muscle sampled by biopsy. Twenty-three healthy young men (24.5 ± 5.0 yr, 76.2 ± 8.3 kg) were studied in groups of four or five. First, the effects of flooding with phenylalanine, threonine, or arginine (all at 0.05 g/kg body wt) on the incorporation of tracer [13C]leucine were studied. Then the effects of flooding with labeled [13C]glycine [0.1 g/kg body wt, 20 atoms percent excess (APE)] and [13C]serine (0.05 g/kg body wt, 15 APE) on the incorporation of simultaneously infused [13C]leucine were investigated. When a large dose of phenylalanine or threonine was administered, incorporation of the tracer leucine was significantly increased (from 0.036 to 0.067 %/h and 0.037 to 0.070 %/h, respectively; each P < 0.01). However, when arginine, glycine, or serine was administered as a flooding dose, no stimulation of tracer leucine incorporation could be observed. These results, together with those previously obtained, suggest that large doses of individual essential, but not nonessential, amino acids are able to stimulate incorporation of constantly infused tracer amino acids into human muscle protein.

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