Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I

2000 ◽  
Vol 278 (6) ◽  
pp. E1133-E1143 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Leonard S. Jefferson ◽  
Scot R. Kimball ◽  
Thomas C. Vary
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Translational Efficiency ◽  
Time Points ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Igf I ◽  
Vascular Catheters

The present study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle after administration of endotoxin (LPS). Rats implanted with vascular catheters were injected intravenously with a nonlethal dose of Escherichia coli LPS, and samples were collected at 4 and 24 h thereafter; pair-fed control animals were also included. The rate of muscle (gastrocnemius) protein synthesis in vivo was reduced at both time points after LPS administration. LPS did not alter tissue RNA content, but the translational efficiency was consistently reduced at both time points. To identify mechanisms responsible for regulating translation, we examined several eukaryotic initiation factors (eIFs). The content of eIF2α or the amount of eIF2α in the phosphorylated form did not change in response to LPS. eIF2B activity was decreased in muscle 4 h post-LPS but activity returned to control values by 24 h. A decrease in the relative amount of eIF2Bα protein was not responsible for the LPS-induced reduction in eIF2B activity. LPS also markedly altered the distribution of eIF4E in muscle. Compared with control values, LPS-treated rats demonstrated 1) a transient increase in binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF4E, 2) a transient decrease in the phosphorylated γ-form of 4E-BP1, and 3) a sustained decrease in the amount of eIF4G associated with eIF4E. LPS also decreased insulin-like growth factor (IGF) I protein and mRNA expression in muscle at both times. A significant linear relationship existed between muscle IGF-I and the rate of protein synthesis or the amount of eIF4E bound to eIF4G. In summary, these data suggest that LPS impairs muscle protein synthesis, at least in part, by decreasing translational efficiency, resulting from an impairment in translation initiation associated with alterations in both eIF2B activity and eIF4E availability.

TNF-binding protein ameliorates inhibition of skeletal muscle protein synthesis during sepsis

1999 ◽  
Vol 276 (4) ◽  
pp. E611-E619 ◽  
Author(s):  
Robert Cooney ◽  
Scot R. Kimball ◽  
Rebecca Eckman ◽  
George Maish ◽  
Margaret Shumate ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Content ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Binding Protein ◽  
Initiation Factor ◽  
Translational Efficiency ◽  
Skeletal Muscle Protein ◽  
Muscle Weight ◽  
Initiation Factors

We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP. Saline (1.0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis. The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later. Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency. Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight. Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis. We also assessed potential mechanisms regulating translational efficiency. The phosphorylation state of p70S6 kinase was not altered by sepsis. Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bε (eIF2Bε), but not eIF2α. The decrease in eIF2Bε content was prevented by treatment of septic rats with TNFBP. TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process. The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.

IGF-I/IGFBP-3 ameliorates alterations in protein synthesis, eIF4E availability, and myostatin in alcohol-fed rats

2004 ◽  
Vol 286 (6) ◽  
pp. E916-E926 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Elisabeth Svanberg ◽  
Thomas C. Vary
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Initiation Factor ◽  
Translational Efficiency ◽  
Binary Complex ◽  
Chronic Alcohol ◽  
Anabolic Hormone ◽  
Igf I ◽  
Igfbp 3

Chronic alcohol consumption decreases the concentration of the anabolic hormone IGF-I, and this change is associated with impaired muscle protein synthesis. The present study evaluated the ability of IGF-I complexed with IGF-binding protein (IGFBP)-3 to modulate the alcohol-induced inhibition of muscle protein synthesis in gastrocnemius. After 16 wk on an alcohol-containing diet, either the IGF-I/IGFBP-3 binary complex (BC) or saline was injected two times daily for three consecutive days. After the final injection of BC (3 h), plasma IGF-I concentrations were elevated in alcohol-fed rats to values not different from those of similarly treated control animals. Alcohol feeding decreased the basal rate of muscle protein synthesis by limiting translational efficiency. BC treatment of alcohol-fed rats increased protein synthesis back to basal control values, but the rate remained lower than that of BC-injected control rats. The BC partially reversed the alcohol-induced decrease in the binding of eukaryotic initiation factor (eIF)4E with eIF4G. This change was associated with reversal of the alcohol-induced dephosphorylation of eIF4G but was independent of changes in the phosphorylation of either 4E-BP1 or eIF4E. However, BC reversed the alcohol-induced increase in IGFBP-1 and muscle myostatin, known negative regulators of IGF-I action and muscle mass. Hence, exogenous IGF-I, administered as part of a BC to increase its circulating half-life, can in part reverse the decreased protein synthesis observed in muscle from chronic alcohol-fed rats by stimulating selected components of translation initiation. The data support the role of IGF-I as a mediator of chronic alcohol myopathy in rats.

Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle

2005 ◽  
Vol 289 (3) ◽  
pp. E382-E390 ◽  
Author(s):  
Ly Q. Hong-Brown ◽  
Anne M. Pruznak ◽  
Robert A. Frost ◽  
Thomas C. Vary ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Hiv Protease ◽  
Plasma Testosterone ◽  
Translational Efficiency ◽  
Model Assessment

The HIV protease inhibitor indinavir adversely impairs carbohydrate and lipid metabolism, whereas its influence on protein metabolism under in vivo conditions remains unknown. The present study tested the hypothesis that indinavir also decreases basal protein synthesis and impairs the anabolic response to insulin in skeletal muscle. Indinavir was infused intravenously for 4 h into conscious rats, at which time the homeostasis model assessment of insulin resistance was increased. Indinavir decreased muscle protein synthesis by 30%, and this reduction was due to impaired translational efficiency. To identify potential mechanisms responsible for regulating mRNA translation, several eukaryotic initiation factors (eIFs) were examined. Under basal fasted conditions, there was a redistribution of eIF4E from the active eIF4E·eIF4G complex to the inactive eIF4E·4E-BP1 complex, and this change was associated with a marked decrease in the phosphorylation of 4E-BP1 in muscle. Likewise, indinavir decreased constitutive phosphorylation of eIF4G and mTOR in muscle, but not S6K1 or the ribosomal protein S6. In contrast, the ability of a maximally stimulating dose of insulin to increase the phosphorylation of PKB, 4E-BP1, S6K1, or mTOR was not altered 20 min after intravenous injection. Indinavir increased mRNA expression of the ubiquitin ligase MuRF1, but the plasma concentration of 3-methylhistidine remained unaltered. These indinavir-induced changes were associated with a marked reduction in the plasma testosterone concentration but were independent of changes in plasma levels of IGF-I, corticosterone, TNF-α, or IL-6. In conclusion, indinavir acutely impairs basal protein synthesis and translation initiation in skeletal muscle but, in contrast to muscle glucose uptake, does not impair insulin-stimulated signaling of protein synthetic pathways.

IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids

1996 ◽  
Vol 270 (1) ◽  
pp. E60-E66 ◽  
Author(s):  
R. Jacob ◽  
X. Hu ◽  
D. Niederstock ◽  
S. Hasan ◽  
P. H. McNulty ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Plasma Insulin ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Amino Acid Replacement ◽  
Igf I ◽  
Awake Rat

Infusion of insulin-like growth factor I (IGF-I) lowers plasma amino acid and insulin concentrations, which may limit the capacity of IGF-I to promote muscle protein synthesis in vivo. We measured heart and skeletal muscle incorporation of continuously infused L-[ring-2,6-3H]phenylalanine in awake postabsorptive rats receiving 4-h intravenous infusions of saline (n = 11), IGF-I (1 microgram.kg-1.min-1) with (n = 10) or without (n = 11) amino acid replacement, or IGF-I with insulin replacement (n = 8). There were no significant increases in muscle protein synthesis during the infusion of IGF-I alone, which was associated with decreases in both plasma insulin (52 +/- 5%, P < 0.001) and amino acids (25 +/- 5%, P < 0.05). When IGF-I was given together with amino acids, protein synthesis was significantly increased in gastrocnemius (4.7 +/- 0.4 vs. 2.5 +/- 0.3%/day, P < 0.001), oblique (4.5 +/- 0.4 vs. 2.8 +/- 0.4%/day, P < 0.05), and soleus (8.8 +/- 0.7 vs. 6.4 +/- 0.3%/day, P < 0.01) and tended to be higher than saline control values in heart (10.9 +/- 0.9 vs. 8.8 +/- 0.7%/day, P = 0.08). Amino acid replacement prevented plasma concentrations from falling and also blunted the decline in plasma insulin (22 +/- 5%, P < 0.01 vs. IGF-I alone). When IGF-I and insulin replacement were given, protein synthesis was increased in heart (13.0 +/- 0.6%/day), gastrocnemius (4.7 +/- 0.4%/day), and oblique (4.5 +/- 0.4%/day) (P < 0.001 for each, compared with saline). We conclude that the action of IGF-I to acutely stimulate muscle protein synthesis in the awake rat is limited by the fall in circulating insulin and/or amino acid concentrations that accompanies IGF-I infusion in vivo and is prevented by co-infusion of insulin or amino acids.

IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis

1996 ◽  
Vol 270 (3) ◽  
pp. E430-E437 ◽  
Author(s):  
C. H. Lang ◽  
J. Fan ◽  
R. Cooney ◽  
T. C. Vary
Keyword(s):  
Protein Synthesis ◽  
Receptor Antagonist ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Abdominal Sepsis ◽  
Constant Infusion ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Igf I

The purpose of the present investigation was to determine whether endogenously produced interleukin (IL)-1 mediates the changes in insulin-like growth factor (IGF) I and IGF binding proteins (IGFBP) induced by chronic abdominal sepsis in rats and to correlate the changes in the IGF system with the alternations in protein synthesis. A constant infusion of IL-1 receptor antagonist (IL-1ra) was begun after the induction of sepsis and was continued for 5 days. Sepsis decreased IGF-I levels in the blood, liver, and gastrocnemius muscle, increased the content in the kidney, and did not alter IGF-I levels in heart, jejunum, and spleen. IL-1ra attenuated the sepsis-induced decrease in plasma IGF-I and completely prevented the changes in IGF-I observed in liver, kidney, and the gastrocnemius. IGFBP-1 was increased in the blood, liver, and muscle of septic rats. IL-1ra prevented this increase in IGFBP-1 in blood and liver but not in muscle. The rate of in vivo protein synthesis was decreased in the gastrocnemius and kidney and unaltered in the heart, liver, jejunum, and spleen. A strong linear correlation existed between levels of IGF-I and the rate of protein synthesis determined simultaneously in the gastrocnemius. These results provide evidence for the role of IL-1 as an endogenous mediator of the sepsis-induced changes in IGF-I and IGFBP-1 and suggest that the accompanying changes in muscle protein synthesis are partially mediated via changes in IGF-I.

scholarly journals Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3922-3933 ◽  
Author(s):  
Charles H. Lang ◽  
Thomas C. Vary ◽  
Robert A. Frost
Keyword(s):  
Protein Synthesis ◽  
Plasma Concentration ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Binding Protein ◽  
Igf I ◽  
Igf Binding ◽  
Fast Twitch ◽  
Igf Binding Protein

Abstract This study examined whether the acute elevation of IGF-binding protein-1 (IGFBP-1) decreases the plasma free IGF-I concentration and alters in vivo rates of muscle protein synthesis and glucose uptake. The plasma concentration of human IGFBP-1 was increased to approximately 95 ng/ml in conscious catheterized rats infused iv with human IGFBP-1 for 4 h. Infusion of IGFBP-1 also increased the concentration of endogenous (e.g. rat) IGFBP-1 in the blood, and this response was associated with a 2- to 3-fold elevation of IGFBP-1 mRNA in liver and kidney. IGFBP-1 did not significantly alter the plasma concentration of total IGF-I, but decreased circulating free IGF-I levels by about 50%. IGFBP-1 decreased protein synthesis in the predominantly fast-twitch gastrocnemius muscle (20%), and this change resulted from a decreased translational efficiency that was associated with a decreased phosphorylation of S6K1, but not 4E-BP1. Complementary studies demonstrated that IGFBP-1 also decreased the rates of protein synthesis under basal conditions and in response to stimulation by IGF-I when added in vitro to the fast-twitch epitrochlearis muscle. In contrast, IGFBP-1 did not alter in vivo-determined rates of protein synthesis in the slow-twitch soleus muscle, heart, liver, or kidney. The infusion of IGFBP-1 did not significantly alter the plasma glucose or lactate concentration or the whole body rate of glucose production or disposal. The above-mentioned changes were not mediated indirectly by changes in the plasma insulin or corticosterone concentrations, decreased high energy phosphate content in muscle, or hepatoxicity produced by the infused IGFBP-1. These results demonstrate that acute in vivo elevation in IGFBP-1, of the magnitude observed in various catabolic conditions, is capable of selectively decreasing protein synthesis in fast-twitch skeletal muscle and up-regulating the hepatic and renal syntheses of IGFBP-1 per se. Hence, elevations in circulating and tissue levels of IGFBP-1 may be an important mediator for the muscle catabolism observed in various stress conditions.

Chronic effects of β2 agonists on body composition and protein synthesis in the rat

1984 ◽  
Vol 4 (1) ◽  
pp. 83-91 ◽  
Author(s):  
P. W. Emery ◽  
N. J. Rothwell ◽  
M. J. Stock ◽  
P. D. Winter
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Binding Capacity ◽  
Body Weight Gain ◽  
Muscle Protein Synthesis ◽  
Body Protein ◽  
Fractional Rate ◽  
Brown Adipose ◽  
Β2 Agonists

Chronic treatment of rats with the β2-adrenergic agonists clenbuterol and fenoterol over 16–19 d raised energy intake, expenditure, and body weight gain but did not affect fat or energy deposition, and body protein gain was increased by 50 and 18%, respectively. Both drugs increased the protein content and mitochondrial GDP-binding capacity of brown adipose tissue. Clenbuterol did not affect plasma insulin, growth hormone, or triiodothyronine levels, although insulin levels were reduced by fenoterol. Both drugs caused hypertrophy of skeletal muscle (gastrocnemius), and muscle protein synthesis in vivo (fractional rate) was elevated by 34 and 26% in clenbuterol and fenoteroltreated rats, respectively.

Role of insulin and IGF-I in activation of muscle protein synthesis after oral feeding

1996 ◽  
Vol 270 (4) ◽  
pp. E614-E620 ◽  
Author(s):  
E. Svanberg ◽  
H. Zachrisson ◽  
C. Ohlsson ◽  
B. M. Iresjo ◽  
K. G. Lundholm
Keyword(s):  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Oral Feeding ◽  
Myofibrillar Proteins ◽  
Diabetic Mice ◽  
Igf I ◽  
Stimulation Of

The aim was to evaluate the role of insulin and insulin-like growth factor I (IGF-I) in activation of muscle protein synthesis after oral feeding. Synthesis rate of globular and myofibrillar proteins in muscle tissue was quantified by a flooding dose of radioactive phenylalanine. Muscle tissue expression of IGF-I mRNA was measured. Normal (C57 Bl) and diabetic mice (type I and type II) were subjected to an overnight fast (18 h) with subsequent refeeding procedures for 3 h with either oral chow intake or provision of insulin, IGF-I, glucose, and amino acids. Anti-insulin and anti-IGF-I were provided intraperitoneally before oral refeeding in some experiments. An overnight fast reduced synthesis of both globular (38 +/- 3%) and myofibrillar proteins (54 +/- 3%) in skeletal muscles, which was reversed by oral refeeding. Muscle protein synthesis, after starvation/ refeeding, was proportional and similar to changes in skeletal muscle IGF-I mRNA expression. Diabetic mice responded quantitatively similarly to starvation/refeeding in muscle protein synthesis compared with normal mice (C57 Bl). Both anti-insulin and anti-IGF-I attenuated significantly the stimulation of muscle protein synthesis in response to oral feeding, whereas exogenous provision of either insulin or IGF-I to overnight-starved and freely fed mice did not clearly stimulate protein synthesis in skeletal muscles. Our results support the suggestion that insulin and IGF-I either induce or facilitate the protein synthesis machinery in skeletal muscles rather than exerting a true stimulation of the biosynthetic process during feeding.

Enhanced response of muscle protein synthesis and plasma insulin to food intake in suckled rats

1993 ◽  
Vol 265 (2) ◽  
pp. R334-R340 ◽  
Author(s):  
T. A. Davis ◽  
M. L. Fiorotto ◽  
H. V. Nguyen ◽  
P. J. Reeds
Keyword(s):  
Protein Synthesis ◽  
Food Intake ◽  
Plasma Insulin ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fed State ◽  
Fasting And Refeeding ◽  
Old Rats ◽  
Amino Acid Concentrations

To compare the sensitivity of muscle protein synthesis to food intake in neonatal and weaned rats, 5- and 16-day-old suckled rats and 28-day-old weaned rats were either fed, fasted for 8-10 h, or refed for 1-4 h after an 8-h fast. Protein synthesis was measured in vivo in soleus and plantaris muscles with a large dose of L-[4-3H]phenylalanine. In fed rats, fractional rates of protein synthesis (KS) decreased with age. Fasting decreased KS, and refeeding increased KS most in 5-day-old animals, less in 16-day-old rats, and least in 28-day-old rats. In 5-day-old rats, there were no differences in KS between soleus and plantaris muscles in the fed state and after fasting and refeeding; at 28 days, KS was higher in soleus than in plantaris in fed rats, and the soleus did not respond to fasting and refeeding. In rats at all three ages, the concentration of most plasma amino acids decreased during fasting; when 5-day-old rats were refed, plasma amino acid concentrations increased, but not to the levels in the fed state. Plasma insulin concentrations increased with age. Plasma insulin concentrations decreased more rapidly with fasting and increased more extensively with refeeding in 5-day-old rats than in older rats. These results suggest that muscle protein synthesis is more responsive to food intake in young suckled rats than in older suckled or weaned rats; this increased responsiveness is accompanied by greater changes in circulating insulin concentrations.

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