Administration of IGF-I In Vivo Stimulates Protein Synthesis and Inhibits Protein Breakdown in Skeletal Muscle Following Burn Injury

Thermal injury is associated with a pronounced catabolic response in skeletal muscle, reflecting inhibited protein synthesis and increased protein breakdown, in particular myofibrillar protein breakdown. Administration of insulin-like growth factor I (IGF-I) has a nitrogen-sparing effect after burn injury, but the influence of this treatment on protein turnover rates in skeletal muscle is not known. In the present study, we examined the effect of IGF-I on muscle protein synthesis and breakdown rates following burn injury in rats. After a 30% total body surface area burn injury or sham procedure, rats were treated with a continuous infusion of IGF-I (3.5 or 7 mg ⋅ kg−1 ⋅ 24 h−1) for 24 h. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Burn injury resulted in increased total and myofibrillar protein breakdown rates and reduced protein synthesis in muscle. The increase in protein breakdown rates was blocked by both doses of IGF-I and the burn-induced inhibition of muscle protein synthesis was partially reversed by the higher dose of the hormone. IGF-I did not influence muscle protein turnover rates in nonburned rats. The results suggest that the catabolic response to burn injury in skeletal muscle can be inhibited by IGF-I.

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Phosphatidylinositol 3-Kinase (PI3K) Signalling Pathway Mediates IGF-I-Induced Inhibition of Protein Breakdown in Skeletal Muscle after Burn Injury

Journal of Burn Care & Rehabilitation ◽

10.1097/00004630-200303002-00130 ◽

2003 ◽

Vol 24 ◽

pp. S107

Author(s):

C. H. Fang ◽

B. Li ◽

J. K. King ◽

P. O. Hasselgren

Keyword(s):

Skeletal Muscle ◽

Burn Injury ◽

Signalling Pathway ◽

Protein Breakdown ◽

Phosphatidylinositol 3 Kinase ◽

Igf I ◽

Pi3k Signalling ◽

Phosphatidylinositol 3

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IGF-I stimulates protein synthesis but does not inhibit protein breakdown in muscle from septic rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.2.r571 ◽

1998 ◽

Vol 274 (2) ◽

pp. R571-R576 ◽

Cited By ~ 12

Author(s):

Scott C. Hobler ◽

Arthur B. Williams ◽

Josef E. Fischer ◽

Per-Olof Hasselgren

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Cecal Ligation ◽

Myofibrillar Protein ◽

Maximal Effect ◽

Protein Breakdown ◽

Breakdown Rates ◽

Igf I ◽

Dose Dependent Fashion ◽

High Concentrations

Sepsis is associated with reduced protein synthesis and increased protein degradation in skeletal muscle. We examined the effects of insulin-like growth factor I (IGF-I) on protein synthesis and breakdown in muscles from nonseptic and septic rats. Sepsis was induced by cecal ligation and puncture; control rats were sham operated. Extensor digitorum longus muscles were incubated in the absence or presence of IGF-I at concentrations ranging from 100 ng/ml to 10 μg/ml. Total and myofibrillar protein breakdown rates were measured as net release of tyrosine and 3-methylhistidine, respectively. Protein synthesis was determined by measuring incorporation of [U-14C]phenylalanine into protein. IGF-I stimulated protein synthesis in a dose-dependent fashion in muscles from both sham-operated and septic rats, with a maximal effect seen at a hormone concentration between 500 and 1,000 ng/ml. IGF-I inhibited total and myofibrillar protein breakdown in muscles from sham-operated rats, whereas in muscles from septic rats, IGF-I had no effect on protein breakdown, even at high concentrations. The results suggest that protein breakdown in skeletal muscle becomes resistant to IGF-I during sepsis and that this resistance reflects a postreceptor defect.

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GH and IGF-I differentially increase protein synthesis in skeletal muscle and jejunum of parenterally fed rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.5.e872 ◽

1996 ◽

Vol 271 (5) ◽

pp. E872-E878 ◽

Cited By ~ 6

Author(s):

H. C. Lo ◽

D. M. Ney

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Body Weight Gain ◽

Serum Insulin ◽

Jejunal Mucosa ◽

Tissue Mass ◽

Tissue Protein ◽

Igf I ◽

Tissue Protein Synthesis

Growth hormone (GH) and insulin-like growth factor I (IGF-I) selectively increase tissue mass. We compared the fractional rate of protein synthesis (Ks in skeletal muscle, jejunal mucosa and muscularis, and liver to investigate the differential effects of GH and IGF-I on tissue protein synthesis. Surgically stressed rats were maintained with hypocaloric total parenteral nutrition (TPN) and given recombinant human (rh) GH (rhGH), rhIGF-I, rhGH + rhIGF-I (800 or 800 + 800 micrograms/day, respectively), or TPN alone. After 3 days, a flooding dose of valine (800 mumol with 5.56 MBq L-[3,4-3H]valine) was administered, and rats were killed 20 min later. Body weight gain, nitrogen retention, and serum IGF-I concentrations confirmed that GH plus IGF-I additively increased anabolism. Serum insulin concentrations were significantly increased by GH and decreased by IGF-I. GH significantly increased Ks in skeletal muscle and jejunal muscularis, IGF-I significantly increased Ks in jejunal mucosa and muscularis, and neither GH nor IGF-I altered Ks in liver. GH and IGF-I differentially increase tissue protein synthesis in vivo.

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Protein synthesis in skeletal muscle and jejunum is more responsive to feeding in 7-than in 26-day-old pigs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.5.e802 ◽

1996 ◽

Vol 270 (5) ◽

pp. E802-E809 ◽

Cited By ~ 69

Author(s):

T. A. Davis ◽

D. G. Burrin ◽

M. L. Fiorotto ◽

H. V. Nguyen

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Protein Synthesis ◽

Plasma Concentrations ◽

Postnatal Life ◽

Tissue Protein ◽

Igf I ◽

Tissue Protein Synthesis ◽

Stimulation Of

The study aimed to determine the developmental changes in the response of peripheral and visceral tissue protein synthesis to feeding during early postnatal life and the associated changes in circulating insulin, insulin-like growth factor (IGF-I), and amino acid concentrations. Tissue protein synthesis was measured in vivo with a large dose of L-[4(-3)H]phenylalanine in 7- and 26-day-old pigs that were either fasted for 24 h or refed for 2.75 h after a 24-h fast. Fractional rates of protein synthesis (Ks) in skeletal muscle, heart, and liver were greater in 7-than in 26-day-old pigs. Refeeding stimulated Ks in skeletal muscle, pancreas, jejunum, and liver of both 7-and 26-day-old pigs. The stimulation of skeletal muscle and jejunal Ks by refeeding was greater in 7- than in 26-day-old pigs. Plasma IGF-I concentrations were lower in 7- than in 26-day-old pigs. Plasma concentrations of insulin and amino acids increased with refeeding. The increase in plasma insulin concentrations with refeeding was greater in 7- than in 26-days-old pigs. These results indicate that the stimulation in skeletal muscle and jejunal protein synthesis by feeding is elevated in young compared with older suckling pigs. This enhanced stimulation of protein synthesis by feeding in neonatal pigs is associated with elevated circulating concentrations of insulin but not amino acids or IGF-I.

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Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.3.e499 ◽

1991 ◽

Vol 260 (3) ◽

pp. E499-E504 ◽

Cited By ~ 22

Author(s):

D. A. Fryburg ◽

R. A. Gelfand ◽

E. J. Barrett

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Growth Hormone ◽

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Skeletal Muscle Protein ◽

Skeletal Muscle Protein Synthesis ◽

Igf I ◽

Normal Humans

The short-term effects of growth hormone (GH) on skeletal muscle protein synthesis and degradation in normal humans are unknown. We studied seven postabsorptive healthy men (age 18-23 yr) who received GH (0.014 micrograms.kg-1.min-1) via intrabrachial artery infusion for 6 h. The effects of GH on forearm amino acid and glucose balances and on forearm amino acid kinetics [( 3H]Phe and [14C]Leu) were determined after 3 and 6 h of the GH infusion. Forearm deep vein GH rose to 35 +/- 6 ng/ml in response to GH, whereas systemic levels of GH, insulin, and insulin-like growth factor I (IGF-I) were unchanged. Forearm glucose uptake did not change during the study. After 6 h, GH suppressed forearm net release (3 vs. 6 h) of Phe (P less than 0.05), Leu (P less than 0.01), total branched-chain amino acids (P less than 0.025), and essential neutral amino acids (0.05 less than P less than 0.1). The effect on the net balance of Phe and Leu was due to an increase in the tissue uptake for Phe (71%, P less than 0.05) and Leu (37%, P less than 0.005) in the absence of any significant change in release of Phe or Leu from tissue. In the absence of any change in systemic GH, IGF-I, or insulin, these findings suggest that locally infused GH stimulates skeletal muscle protein synthesis. These findings have important physiological implications for both the role of daily GH pulses and the mechanisms through which GH can promote protein anabolism.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00065.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. E666-E674 ◽

Cited By ~ 24

Author(s):

Charles H. Lang

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Protein Synthesis ◽

Free Fatty Acids ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Short Term ◽

Lipid Infusion ◽

Igf I ◽

Plasma Ffas

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 ∼25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E·eIF4G complex to the inactive eIF4E·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 Ser307 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.

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Fiber-type composition of nine rat muscles. II. Relationship to protein turnover

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.257.6.e828 ◽

1989 ◽

Vol 257 (6) ◽

pp. E828-E832 ◽

Cited By ~ 12

Author(s):

P. J. Garlick ◽

C. A. Maltin ◽

A. G. Baillie ◽

M. I. Delday ◽

D. A. Grubb

Keyword(s):

Protein Synthesis ◽

Regression Analysis ◽

Protein Turnover ◽

Fiber Type ◽

Female Rats ◽

Protein Breakdown ◽

Fiber Type Composition ◽

Type Composition ◽

Age Regression

Rates of protein synthesis in vivo and fiber-type composition were measured in nine limb muscles of female rats at ages ranging from weaning to 1 yr. In all muscles, there was a decline in protein synthesis with increasing age, mostly as a result of a fall in the RNA content. Rates of protein breakdown and growth were determined in six muscles and these also declined with age. Regression analysis of the data for all ages showed that protein synthesis was correlated with the content of slow oxidative fibers but not with the relative proportions of fast glycolytic to fast oxidative glycolytic fibers.

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