scholarly journals Effect of sepsis on eIE4E availability in skeletal muscle

2000 ◽  
Vol 279 (5) ◽  
pp. E1178-E1184 ◽  
Author(s):  
Thomas C. Vary ◽  
Scot R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Binding Protein ◽  
Abscess Formation ◽  
Sterile Inflammation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Sterile Abscess ◽  
Inhibition Of Protein Synthesis

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius that is not observed in rats with a sterile abscess. The inhibition is associated with an impaired translation initiation. The present study was designed to investigate the effects of sepsis on phosphorylation and availability of eukaryotic initiation factor (eIF)4E in gastrocnemius 5 days after induction of a sterile or septic abscess. Neither sepsis nor sterile inflammation altered the extent of eIF4E phosphorylation. Moreover, no changes in the amount of the binding protein 4E-BP1 associated with eIF4E or in the phosphorylation of 4E-BP1 were observed during sepsis or sterile inflammation. In contrast, sepsis and sterile inflammation caused a reduction in the relative amount of eIF4G bound to eIF4E compared with controls. The diminished amount of eIF4G bound to eIF4E was not the result of a reduced abundance of eIF4E. Sepsis, but not sterile inflammation, caused an increase in the cellular abundance of eIF4E. The results provide evidence that alterations in the eIF4E system are probably not rate controlling for the synthesis of total, mixed proteins in gastrocnemius during sepsis. Instead, on the basis of our previous studies, changes in eIF2B appear to be responsible for limiting protein synthesis in skeletal muscle during sepsis.

Phosphorylation of eukaryotic initiation factor eIF2Bε in skeletal muscle during sepsis

2002 ◽  
Vol 283 (5) ◽  
pp. E1032-E1039 ◽  
Author(s):  
Thomas C. Vary ◽  
Gina Deiter ◽  
Scot R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Glycogen Synthase ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Sterile Inflammation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Skeletal Muscle Protein

We reported that the inhibition of protein synthesis in skeletal muscle during sepsis correlated with reduced eukaryotic initiation factor eIF2B activity. The present studies define changes in eIF2Bε phosphorylation in gastrocnemius of septic animals. eIF2B kinase activity was significantly elevated 175% by sepsis compared with sterile inflammation, whereas eIF2B phosphatase activity was unaffected. Phosphorylation of eIF2Bε-Ser535 was significantly augmented over 2-fold and 2.5-fold after 3 and 5 days and returned to control values after 10 days of sepsis. Phosphorylation of glycogen synthase kinase-3 (GSK-3), a potential upstream kinase responsible for the elevated phosphorylation of eIF2Bε, was significantly reduced over 36 and 41% after 3 and 5 days and returned to control values after 10 days of sepsis. The phosphorylation of PKB, a kinase thought to directly phosphorylate and inactivate GSK-3, was significantly reduced ∼50% on day 3, but not on days 5 or 10, postinfection compared with controls. Treatment of septic rats with TNF-binding protein prevented the sepsis-induced changes in eIF2Bε and GSK-3 phosphorylation, implicating TNF in mediating the effects of sepsis. Thus increased phosphorylation of eIF2Bε via activation of GSK-3 is an important mechanism to account for the inhibition of skeletal muscle protein synthesis during sepsis. Furthermore, the study presents the first demonstration of changes in eIF2Bε phosphorylation in vivo.

scholarly journals The distribution of eukaryotic initiation factor 4E after bouts of resistance exercise is altered by shortening of recovery periods

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
Junya Takegaki ◽  
Riki Ogasawara ◽  
Karina Kouzaki ◽  
Satoshi Fujita ◽  
Koichi Nakazato ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Resistance Exercise ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Related Factors ◽  
Eukaryotic Initiation Factor 4E

Abstract Insufficient duration of recovery between resistance exercise bouts reduces the effects of exercise training, but the influence on muscle anabolic responses is not fully understood. Here, we investigated the changes in the distribution of eukaryotic initiation factor (eIF) 4E, a key regulator of translation initiation, and related factors in mouse skeletal muscle after three successive bouts of resistance exercise with three durations of recovery periods (72 h: conventional, 24 h: shorter, and 8 h: excessively shorter). Bouts of resistance exercise dissociated eIF4E from eIF4E binding protein 1, with the magnitude increasing with shorter recovery. Whereas bouts of resistance exercise with 72 h recovery increased the association of eIF4E and eIF4G, those with shorter recovery did not. Similar results were observed in muscle protein synthesis. These results suggest that insufficient recovery inhibited the association of eIF4E and eIF4G, which might cause attenuation of protein synthesis activation after bouts of resistance exercise.

Insulin stimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G

1997 ◽  
Vol 272 (2) ◽  
pp. C754-C759 ◽  
Author(s):  
S. R. Kimball ◽  
C. V. Jurasinski ◽  
J. C. Lawrence ◽  
L. S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Gastrocnemius Muscle ◽  
Binding Protein ◽  
Fold Increase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Phosphorylated Form ◽  
Stimulation Of

Insulin stimulated protein synthesis in gastrocnemius muscle of perfused rat hindlimb preparations by approximately twofold. The stimulation of protein synthesis was associated with a 12-fold increase in the amount of eukaryotic initiation factor eIF-4G bound to the mRNA cap-binding protein eIF-4E. In part, the increased binding of eIF-4G to eIF-4E was a result of release of eIF-4E bound to the translational regulator, PHAS-I, through a mechanism involving enhanced phosphorylation of PHAS-I. However, the insulin-induced association of eIF-4E and eIF-4G was not due to increased net phosphorylation of eIF-4E because insulin decreased the amount present in the phosphorylated form from 86 to 59% of total eIF-4E. Overall, the results suggest that insulin stimulates protein synthesis in gastrocnemius muscle through a mechanism involving increased binding of eIF-4G to eIF-4E, which is in part due to phosphorylation of PHAS-I, resulting in a release of eIF-4E from the inactive PHAS-I x eIF-4E complex.

Altered expression of eukaryotic initiation factor 2B in skeletal muscle during sepsis

1996 ◽  
Vol 270 (1) ◽  
pp. E43-E50 ◽  
Author(s):  
L. Voisin ◽  
K. Gray ◽  
K. M. Flowers ◽  
S. R. Kimball ◽  
L. S. Jefferson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Altered Expression ◽  
Septic Episode ◽  
Inhibition Of Protein Synthesis ◽  
Fast Twitch

Sepsis causes an inhibition of protein synthesis in skeletal muscles composed of fast-twitch fibers, in part, as a result of a decreased activity of the eukaryotic initiation factor 2B (eIF-2B). In the present study, we investigated the expression of two subunits of eIF-2B, i.e., the beta- and epsilon-subunits during sepsis. The expression of both beta- and epsilon-subunits of eIF-2B in gastrocnemius was decreased approximately 50% from control values during the first 5 days after induction of sepsis. The decreased expression of eIF-2B epsilon during sepsis correlated with similar reductions in eIF-2B epsilon mRNA. Restoration of protein synthesis (10 days postsurgery) was associated with a return of eIF-2B epsilon expression to values observed in control rats. Expression of eIF-2B epsilon was not altered in heart during sepsis or in gastrocnemius from nonseptic abscess animals. Amrinone, which ameliorated the inhibition of protein synthesis during sepsis, also prevented the fall in eIF-2B epsilon protein after 5 days of infection. The data provide evidence that expression of eIF-2B epsilon is markedly influenced in gastrocnemius during the course of the septic episode and support the concept that this change is a mechanism responsible for the inhibition of protein synthesis observed under this condition.

Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats

1993 ◽  
Vol 264 (1) ◽  
pp. E101-E108 ◽  
Author(s):  
A. M. Karinch ◽  
S. R. Kimball ◽  
T. C. Vary ◽  
L. S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Cardiac Muscle ◽  
Casein Kinase Ii ◽  
Diabetic Rats ◽  
Casein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Fast Twitch

Peptide-chain initiation is inhibited in fast-twitch skeletal muscle, but not heart, of diabetic rats. We have investigated mechanisms that might maintain eukaryotic initiation factor (eIF)-2B activity, preventing loss of efficiency of protein synthesis in heart of diabetic rats but not in fast-twitch skeletal muscle. There was no change in the amount or phosphorylation state of eIF-2 in skeletal or cardiac muscle during diabetes. In contrast, eIF-2B activity was decreased in fast-twitch but not slow-twitch muscle from diabetic animals. NADP+ inhibited partially purified eIF-2B in vitro, but addition of equimolar NADPH reversed the inhibition. The NADPH-to-NADP+ ratio was unchanged in fast-twitch muscle after induction of diabetes but was increased in heart of diabetic rats, suggesting that NADPH also prevents inhibition of eIF-2B in vivo. The activity of casein kinase II, which can phosphorylate and activate eIF-2B in vitro, was significantly lower in extracts of fast-twitch, but not cardiac muscle, of diabetic rats compared with controls. The results presented here demonstrate that changes in eIF-2 alpha phosphorylation are not responsible for the effect of diabetes on eIF-2B activity in fast-twitch skeletal muscle. Modulation of casein kinase II activity may be a factor in the regulation of protein synthesis in muscle during acute diabetes. The activity of eIF-2B in heart might be maintained by the increased NADPH/NADP+.

scholarly journals Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation.

1996 ◽  
Vol 16 (10) ◽  
pp. 5450-5457 ◽  
Author(s):  
D Feigenblum ◽  
R J Schneider
Keyword(s):  
Heat Shock ◽  
Translation Initiation ◽  
Binding Protein ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Metaphase Arrest ◽  
Animal Cells ◽  
Eukaryotic Initiation Factor 4E ◽  
Dependent Protein

Cap-dependent protein synthesis in animal cells is inhibited by heat shock, serum deprivation, metaphase arrest, and infection with certain viruses such as adenovirus (Ad). At a mechanistic level, translation of capped mRNAs is inhibited by dephosphorylation of eukaryotic initiation factor 4E (eIF-4E) (cap-binding protein) and its physical sequestration with the translation repressor protein BP-1 (PHAS-I). Dephosphorylation of BP-I blocks cap-dependent translation by promoting sequestration of eIF-4E. Here we show that heat shock inhibits translation of capped mRNAs by simultaneously inducing dephosphorylation of eIF-4E and BP-1, suggesting that cells might coordinately regulate translation of capped mRNAs by impairing both the activity and the availability of eIF-4E. Like heat shock, late Ad infection is shown to induce dephosphorylation of eIF-4E. However, in contrast to heat shock, Ad also induces phosphorylation of BP-1 and release of eIF-4E. BP-1 and eIF-4E can therefore act on cap-dependent translation in either a mutually antagonistic or cooperative manner. Three sets of experiments further underscore this point: (i) rapamycin is shown to block phosphorylation of BP-1 without inhibiting dephosphorylation of eIF-4E induced by heat shock or Ad infection, (ii) eIF-4E is efficiently dephosphorylated during heat shock or Ad infection regardless of whether it is in a complex with BP-1, and (iii) BP-1 is associated with eIF-4E in vivo regardless of the state of eIF-4E phosphorylation. These and other studies establish that inhibition of cap-dependent translation does not obligatorily involve sequestration of eIF-4E by BP-1. Rather, translation is independently regulated by the phosphorylation states of eIF-4E and the 4E-binding protein, BP-1. In addition, these results demonstrate that BP-1 and eIF-4E can act either in concert or in opposition to independently regulate cap-dependent translation. We suggest that independent regulation of eIF-4E and BP-1 might finely regulate the efficiency of translation initiation or possibly control cap-dependent translation for fundamentally different purposes.

IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle

2000 ◽  
Vol 279 (5) ◽  
pp. E1145-E1158 ◽  
Author(s):  
Elisabeth Svanberg ◽  
Robert A. Frost ◽  
Charles H. Lang ◽  
Jorgen Isgaard ◽  
Leonard S. Jefferson ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Binding Protein ◽  
Initiation Factor ◽  
Translational Efficiency ◽  
Binary Complex ◽  
Igf I ◽  
Inhibition Of Protein Synthesis ◽  
Values Assessment ◽  
Igf Binding ◽  
Igfbp 3

The present study evaluated the ability of insulin-like growth factor I (IGF-I) complexed with IGF binding protein-3 (IGFBP-3) to modulate the sepsis-induced inhibition of protein synthesis in gastrocnemius. Beginning 16 h after the induction of sepsis, either the binary complex or saline was injected twice daily via a tail vein, with measurements made 3 and 5 days later. By day 3, sepsis had reduced plasma IGF-I concentrations ∼50% in saline-treated rats. Administration of the binary complex provided exogenous IGF-I to compensate for the sepsis-induced diminished plasma IGF-I. Sepsis decreased rates of protein synthesis in gastrocnemius relative to controls by limiting translational efficiency. Treatment of septic rats with the binary complex for 5 days attenuated the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. Assessment of potential mechanisms regulating translational efficiency showed that neither the sepsis-induced change in gastrocnemius content of eukaryotic initiation factor 2B (eIF2B), the amount of eIF4E associated with 4E binding protein-1 (4E-BP1), nor the phosphorylation state of 4E-BP1 or eIF4E were altered by the binary complex. Overall, the results are consistent with the hypothesis that decreases in plasma IGF-I are partially responsible for enhanced muscle catabolism during sepsis.

Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle

2000 ◽  
Vol 278 (1) ◽  
pp. E76-E82 ◽  
Author(s):  
O. Jameel Shah ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Intraperitoneal Administration ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Nucleotide Exchange ◽  
Α Subunit ◽  
Initiation Factors

Glucocorticoids are diabetogenic factors that not only antagonize the action of insulin in target tissues but also render these tissues catabolic. Therefore, in rats, we endeavored to characterize the effects in skeletal muscle of glucocorticoids on translation initiation, a regulated process that, in part, governs overall protein synthesis through the modulated activities of eukaryotic initiation factors (eIFs). Four hours after intraperitoneal administration of dexamethasone (100 μg/100 g body wt), protein synthesis in skeletal muscle was reduced to 59% of the value recorded in untreated control animals. Furthermore, translation initiation factor eIF4E preferred association with its endogenous inhibitor 4E-BP1 rather than eIF4G. Dexamethasone treatment resulted in dephosphorylation of both 4E-BP1 and the 40S ribosomal protein S6 kinase concomitant with enhanced phosphorylation of eIF4E. Moreover, the guanine nucleotide exchange activity of eIF2B was unaffected as was phosphorylation of the α-subunit of eIF2. Hence glucocorticoids negatively modulate the activation of a subset of the protein synthetic machinery, thereby contributing to the catabolic properties of this class of hormones in vivo.

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