Effect of starvation on initiation of protein synthesis in skeletal muscle and heart.

1978 ◽  
Vol 235 (2) ◽  
pp. E126 ◽  
Author(s):  
D E Rannels ◽  
A E Pegg ◽  
S R Rannels ◽  
L S Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Heart Muscle ◽  
Psoas Muscle ◽  
Peptide Chain ◽  
Initiation Factor ◽  
Ribosomal Subunits ◽  
Chain Initiation ◽  
Rate Limiting

Psoas muscle of rats starved for 2 or 4 days contained increased levels of ribosomal subunits and exhibited reduced rates of protein synthesis in vitro, demonstrating a starvation-induced inhibition of peptide-chain initiation. The activity of an eIF-2-like initiation factor, assayed in postribosomal supernatants, decreased in psoas during starvation, parallel to a 25% reduction in the RNA level. Reduced eIF-2 activity did not result from nucleotide depletion or increased deacylation of initiator tRNA, nor was it abolished by extensive dialysis. Perfusion of psoas muscle in the presence of insulin reversed the starvation-induced block in peptide-chain initiation, but did not alter the activity of eIF-2 or level of RNA. Furthermore, heart muscle did not manifest a starvation-induced block in peptide-chain initiation even though the activity of eIF-2 and the level of RNA decreased as a result of food deprivation. Thus loss of eIF 2 activity in psoas and heart did not parallel changes in peptide-chain initiation but was associated with a reduction in tissue RNA. These results indicate that the level of eIF-2 is not rate-limiting for peptide-chain initiation under the conditions tested in this study.

Regulation of peptide-chain initiation in muscle during sepsis by interleukin-1 receptor antagonist

1996 ◽  
Vol 271 (3) ◽  
pp. E513-E520 ◽  
Author(s):  
T. C. Vary ◽  
L. Voisin ◽  
R. N. Cooney
Keyword(s):  
Protein Synthesis ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Peptide Chain ◽  
Initiation Factor ◽  
Translational Efficiency ◽  
Ribosomal Subunits ◽  
Chain Initiation ◽  
Interleukin 1 Receptor Antagonist ◽  
Inhibition Of Protein Synthesis

The mechanism by which interleukin-1 (IL-1) regulates protein synthesis in skeletal muscle during hypermetabolic sepsis in rats was investigated. Treatment of septic rats with a specific interleukin-1 receptor antagonist (IL-1ra) prevented the sepsis-induced inhibition of protein synthesis and translational efficiency in gastrocnemius. Analysis of ribosomal subunits revealed that the increase in free 40S and 60S ribosomal subunits observed in septic rats was prevented by infusion of IL-1ra, indicating peptide-chain initiation was maintained at control values. The failure of sepsis to inhibit peptide-chain initiation after infusion of IL-1ra correlated with a maintenance of the epsilon-subunit of eukaryotic initiation factor (eIF) 2B (eIF-2B epsilon) protein at control values. The alterations in the eIF-2B epsilon protein content in gastrocnemius of septic rats treated with or without IL-1ra were associated with corresponding changes in the abundance of eIF 2B epsilon mRNA. The results provide evidence that infusion of IL-1ra attenuates the sepsis-induced inhibition of protein synthesis by preventing the inhibition of peptide-chain initiation and downregulation of eIF-2B expression during sepsis.

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+.

Effects of diabetes on protein synthesis in fast- and slow-twitch rat skeletal muscle

1980 ◽  
Vol 239 (1) ◽  
pp. E88-E95 ◽  
Author(s):  
K. E. Flaim ◽  
M. E. Copenhaver ◽  
L. S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Peptide Chain ◽  
Fiber Types ◽  
Chain Initiation ◽  
Rapid Reversal ◽  
Slow Twitch ◽  
Fast Twitch

The effects of acute (2-day) and long-term (7-day) diabetes on rates of protein synthesis, peptide-chain initiation, and levels of RNA were examined in rat skeletal muscles that are known to have differing proportions of the three fiber types: fast-twitch white, fast-twitch red, and slow-twitch red. Short-term diabetes resulted in a 15% reduction in the level of RNA in all the muscles studied and an impairment in peptide-chain initiation in muscles with mixed fast-twitch fibers. In contrast, the soleus, a skeletal muscle with high proportions of slow-twitch red fibers, showed little impairment in initiation. When the muscles were perfused as a part of the hemicorpus preparation, addition of insulin to the medium caused a rapid reversal of the block in initiation in mixed fast-twitch muscles but had no effect in the soleus. The possible role of fatty acids in accounting for these differences is discussed. Long-term diabetes caused no further reduction in RNA, but resulted in the development of an additional impairment to protein synthesis that also affected the soleus and that was not corrected by perfusion with insulin. The defect resulting from long-term diabetes may involve elongation or termination reactions.

scholarly journals Effects of starvation, diabetes and acute insulin treatment on the regulation of polypeptide-chain initiation in rat skeletal muscle

1984 ◽  
Vol 223 (3) ◽  
pp. 687-696 ◽  
Author(s):  
C S Harmon ◽  
C G Proud ◽  
V M Pain
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Polypeptide Chain ◽  
Ribosomal Subunit ◽  
Diabetic Rats ◽  
Initiation Factor ◽  
Chain Initiation ◽  
Low Concentrations ◽  
40S Ribosomal Subunit

The rate of protein synthesis in skeletal muscle is greatly decreased in response to diabetes and starvation. Analysis of polyribosome profiles indicates that polypeptide-chain initiation is impaired under these conditions. To identify the step in initiation that is affected, we assayed the incorporation of [35S]methionyl-tRNAfMet into [35S]methionyl-tRNAfMet . 40S-ribosomal-subunit initiation complexes in cell-free extracts based on postmitochondrial supernatants prepared from gastrocnemius muscle. Extracts from either starved or diabetic rats were 30-40% less active in forming these complexes compared with those derived from fed or insulin-maintained controls respectively. This change could be reversed by treatment of either starved or diabetic rats with insulin in vivo 30 min before death. Formation of 40S initiation complexes by extracts from either fed or starved rats could be stimulated by the addition of exogenous purified initiation factor eIF-2, but extracts from starved or diabetic rats were more sensitive than controls to stimulation by low concentrations of the factor. These results provide evidence for the acute regulation by insulin of protein synthesis in skeletal muscle at the level of polypeptide-chain initiation, and suggest that in this tissue, as in certain other eukaryotic systems, control of initiation appears to be mediated by changes in the activity of initiation factor eIF-2.

Aminoacylation of initiator methionyl-tRNA(i) under conditions inhibitory to initiation of protein synthesis

1993 ◽  
Vol 264 (2) ◽  
pp. E257-E263 ◽  
Author(s):  
K. M. Ojamaa ◽  
S. R. Kimball ◽  
L. S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Rat Liver ◽  
Diabetic Rats ◽  
Peptide Chain ◽  
Perfused Rat Liver ◽  
Chain Initiation ◽  
Total Rna ◽  
Tissue Content ◽  
Total Tissue

Inhibition of protein synthesis in perfused rat liver deprived of either methionine or tryptophan results from a defect in peptide-chain initiation. Similarly, the decreased rate of protein synthesis in liver from rats deprived of food for 24 h and in skeletal muscle after 2 days of diabetes results from a defect in initiation. In the present study, the tissue content of tRNA(iMet) and its level of aminoacylation were measured in these conditions to determine whether methionyl-tRNA(iMet) formation is a mechanism involved in the regulation of initiation. The extent of aminoacylation of tRNA(iMet) in livers perfused with supplemented medium or medium deficient in either methionine or tryptophan was 64 +/- 2, 61 +/- 3, and 66 +/- 2% of the total accepting activity, respectively. The total tissue content of tRNA(iMet), expressed as a percentage of total RNA, was 1.7 +/- 0.1, 1.6 +/- 0.1, and 1.6 +/- 0.1 for the three conditions, respectively. In livers from starved rats, the extent of aminoacylation of tRNA(iMet) was 80 +/- 7% and the total tissue content of tRNA(iMet) was 1.9 +/- 0.1% compared with control values of 82 +/- 6 and 2.0 +/- 0.1%, respectively. In skeletal muscle from diabetic rats, the extent of aminoacylation of tRNA(iMet) was 79 +/- 4% and the total tissue content of tRNA(iMet) was 2.0 +/- 0.3% compared with values of 79 +/- 5 and 2.0 +/- 0.2% for control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of eukaryotic initiation factor-2 expression during sepsis

1994 ◽  
Vol 266 (2) ◽  
pp. E193-E201 ◽  
Author(s):  
T. C. Vary ◽  
C. V. Jurasinski ◽  
A. M. Karinch ◽  
S. R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Sterile Inflammation ◽  
Peptide Chain ◽  
Initiation Factor ◽  
Control Analysis ◽  
Eukaryotic Initiation Factor ◽  
Chain Initiation ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2 ◽  
Fast Twitch

Protein synthesis is stimulated at the level of peptide chain initiation in livers from rats with a sterile or septic abscess. In contrast, peptide chain initiation is inhibited in fast-twitch skeletal muscles from septic rats. We investigated the possible mechanisms responsible for these differential changes in peptide chain initiation between liver and skeletal muscle during sepsis by measuring the cellular content of eukaryotic initiation factor-2 (eIF-2), the extent of phosphorylation of the alpha-subunit of eIF-2, and the activity of eIF-2B. In skeletal muscle, neither the eIF-2 content nor the extent of phosphorylation of eIF-2 alpha was altered during sepsis. However, a significant decrease (P < 0.001) in eIF-2B activity was observed in fast-twitch muscles. In liver, neither the extent of phosphorylation of eIF-2 alpha nor the activity of eIF-2B was different in rats with a sterile or septic abscess compared with control. However, the amount of eIF-2 in liver was increased in both sterile inflammation and sepsis. The relative abundance of eIF-2 alpha mRNA was not increased in either condition compared with control. Analysis of the distribution of eIF-2 alpha mRNA from control rats revealed that only approximately 40% of the message was associated with polysomes. Sterile inflammation or sepsis caused a 50% increase in the proportion of eIF-2 alpha mRNA associated with the polysomes compared with control.(ABSTRACT TRUNCATED AT 250 WORDS)

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