Mechanism of IL-1 induced inhibition of protein synthesis in skeletal muscle.
Chronic interleukin (IL)-1 administration is associated with negative nitrogen balance and the loss of lean body mass. To elucidate the molecular mechanism(s) by which IL-1 modulates protein metabolism in muscle, we investigated the effects of chronic (6 day) IL-1alpha infusion on protein synthesis in Individual muscles (gastrocnemius, soleus, heart) compared with saline-infused control rats. IL-1 significantly decreased muscle weight, protein content, and the rate of protein synthesis in gastrocnemius (fast-twitch muscle). IL-1 had no effect on these parameters in the heart, whereas only the rate of protein synthesis was reduced in soleus (slow-twitch muscle). The reduction in gastrocnemius protein synthesis was not the result of a decrease in total RNA content, but was associated with a diminished translational efficiency. The diminished translational efficiency correlated with a 40% reduction in the epsilon-subunit of eukaryotic initiation factor 2B (elF2Bepsilon) in gastrocnemius from IL-1 -treated animals. However, the content of the alpha-subunit of elF2 (elF2alpha) was unaffected. In contrast, the elF2alpha content in heart was increased by IL-1, although elF2Bepsilon levels were unchanged. Reductions in skeletal muscle protein synthesis were not associated with a concomitant reduction in circulating or tissue content of insulin-like growth factor I. In summary, the IL-1-induced decrease in gastrocnemius protein synthesis appears to be regulated at the level of RNA translation via a reduction in elF2Bepsilon. These findings support a regulatory role for IL-1 as a mediator of muscle protein synthesis and the alterations in body composition observed in catabolic states where this cytokine is overexpressed.
Cooney
R N
RN
Department of Surgery, Pennsylvania State University, College of Medicine, Hershey 17033, USA.
Maish
G O
GO
Gilpin
T
T
Shumate
M L
ML
Lang
C H
CH
Vary
T C
TC
D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D020662:Guanine Nucleotide Exchange Factors; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D020662:Guanine Nucleotide Exchange Factors; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D007375:Interleukin-1; D011506:Proteins; D012313:RNA; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003345:Corticosterone