Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs.
In the present study, differential responses of regulatory proteins involved in translation initiation in skeletal muscle and liver during sepsis were studied in neonatal pigs treated with lipopolysaccharide (LPS). LPS did not alter eukaryotic initiation factor (eIF) 2B activity in either tissue. In contrast, binding of eIF4G to eIF4E to form the active mRNA-binding complex was repressed in muscle and enhanced in liver. Phosphorylation of eIF4E-binding protein, 4E-BP1, and ribosomal protein S6 kinase, S6K1, was reduced in muscle during sepsis but increased in liver. Finally, changes in 4E-BP1 and S6K1 phosphorylation were associated with altered phosphorylation of the protein kinase mammalian target of rapamycin (mTOR). Overall, the results suggest that translation initiation in both skeletal muscle and liver is altered during neonatal sepsis by modulation of the mRNA-binding step through changes in mTOR activation. Moreover, the LPS-induced changes in factors that regulate translation initiation are more profound than previously reported changes in global rates of protein synthesis in the neonate. This finding suggests that the initiator methionyl-tRNA-rather than the mRNA-binding step in translation initiation may play a more critical role in maintaining protein synthesis rates in the neonate during sepsis.
Kimball
Scot R
SR
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA. skimball@psu.edu
Orellana
Renán A
RA
O'Connor
Pamela M J
PM
Suryawan
Agus
A
Bush
Jill A
JA
Nguyen
Hanh V
HV
Thivierge
M Carole
MC
Jefferson
Leonard S
LS
Davis
Teresa A
TA
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D039603:Eukaryotic Initiation Factor-4G; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D012333:RNA, Messenger; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases