Diminished ERK 1/2 and p38 MAPK phosphorylation in skeletal muscle during sepsis.
Sepsis induces weight loss and the loss of skeletal muscle proteins, in part through an inhibition of protein synthesis secondary to an inhibition of the key steps controlling mRNA translation in skeletal muscle. We have previously shown that sepsis decreases the phosphorylation of eIF4E. The present study examines the phosphorylation of Erk 1/2 MAPK and p38 MAPK in skeletal muscle of rats with a chronic (5-day) intra-abdominal septic abscess. Mnk1 catalyzes the phosphorylation of eIF4E, and Mnk1 is activated by phosphorylation via Erk1/2 MAPK and p38 MAPK. Sepsis resulted in a significant decrease in the steady-state phosphorylation of Erk 1/2 and p38 MAPKs compared with sterile inflammation. To examine the mediators responsible for decreased phosphorylation of Erk 1/2 and p38 MAPKs, rats were treated with TNF binding protein (TNFbp) or infused for 24 h with TNF. Treatment of septic rats with TNFbp resulted in an increase in the phosphorylation of both Erk 1/2 and p38 MAPKs in skeletal muscle. This was associated with enhanced phosphorylation of eIF4E. In contrast, constant intravenous infusion of TNF-alpha for 24 h resulted in a complete inhibition of p38 MAPK phosphorylation while Erk 1/2 MAPK phosphorylation was increased. The net effect was a modest increase in eIF4E phosphorylation. The results suggest altered regulation of Erk 1/2 and p38 MAPK signal translation pathways by endogenously produced TNF, or some compound dependent on TNF may modulate, in part, the phosphorylation state of eIF4E in skeletal muscle during sepsis.
Vary
Thomas C
TC
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. tvary@psu.edu
Deiter
Gina
G
Lang
Charles H
CH
D000818:Animals; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I; D018805:Sepsis / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D053319:Tumor Necrosis Factor Decoy Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases