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Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I
C H Lang1, R A Frost, L S Jefferson
1Departments of Cellular and Molecular Physiology, and Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
Abstract:
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 eIF2alpha or the amount of eIF2alpha 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 eIF2Balpha 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 gamma-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.
Insights
Endotoxin (LPS) administration inhibits skeletal muscle protein synthesis by reducing translational efficiency. This occurs due to impaired translation initiation, affecting eukaryotic initiation factors and insulin-like growth factor I.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Sepsis-induced muscle protein synthesis inhibition is a significant clinical concern.
- Understanding the molecular mechanisms is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the mechanisms by which endotoxin (LPS) inhibits skeletal muscle protein synthesis.
- To identify key molecular players involved in the regulation of translation initiation.
Main Methods:
- Rats were intravenously injected with Escherichia coli LPS.
- Muscle samples were collected at 4 and 24 hours post-injection for analysis.
- Assessed protein synthesis rates, RNA content, translational efficiency, and eukaryotic initiation factors (eIFs).
Main Results:
- LPS administration reduced skeletal muscle protein synthesis and translational efficiency at both 4 and 24 hours.
- While eIF2alpha levels and phosphorylation remained unchanged, eIF2B activity decreased at 4 hours post-LPS.
- LPS altered eIF4E availability by affecting its interaction with 4E-binding protein-1 (4E-BP1) and eIF4G, and decreased insulin-like growth factor I (IGF-I).
Conclusions:
- LPS impairs skeletal muscle protein synthesis primarily by reducing translational efficiency.
- This impairment stems from defects in translation initiation, involving altered eIF2B activity and eIF4E availability.
- IGF-I levels correlate with protein synthesis rates and eIF4E-eIF4G association, suggesting its role in LPS-induced muscle catabolism.