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Departments of Cellular and Molecular Physiology, and Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
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 eIF2
or the amount of eIF2 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 eIF2B 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
-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.
eukaryotic initiation factors; eukaryotic initiation factor 2; eukaryotic initiation factor 4E; peptide-chain initiation; lipopolysaccharide; heart; liver; insulin-like growth factor I; rats
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