PMID- 15701678
OWN - NLM
STAT- MEDLINE
DCOM- 20050726
LR  - 20161124
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 289
IP  - 1
DP  - 2005 Jul
TI  - Acute treatment with TNF-alpha attenuates insulin-stimulated protein synthesis in 
      cultures of C2C12 myotubes through a MEK1-sensitive mechanism.
PG  - E95-104
AB  - Insulin and TNF-alpha exert opposing effects on skeletal muscle protein synthesis 
      that are mediated in part by the rapamycin-sensitive mammalian target of 
      rapamycin (mTOR) pathway and the PD-98059-sensitive, extracellular 
      signal-regulated kinase (ERK)1/2 pathway. The present study examined the separate 
      and combined effects of insulin (INS), TNF, PD-98059, or dnMEK1 adenovirus on the 
      translational control of protein synthesis in C(2)C(12) myotubes. Cultures were 
      treated with INS, TNF, PD-98059, dnMEK1, or a combination of INS + TNF with 
      PD-98059 or dnMEK1. INS stimulated protein synthesis, enhanced eIF4E.eIF4G 
      association, and eIF4G phosphorylation and repressed eIF4E.4E-BP1 association vs. 
      control. INS also promoted phosphorylation of ERK1/2, S6K1, and 4E-BP1 and 
      dephosphorylation of eIF4E. TNF alone did not have an effect on protein synthesis 
      (vs. control), eIF4E.eIF4G association, or the phosphorylation of eIF4G, S6K1, or 
      4E-BP1, although it transiently increased ERK1/2 and eIF4E phosphorylation. When 
      myotubes were treated with TNF + INS, the cytokine blocked the insulin-induced 
      stimulation of protein synthesis. This appeared to be due to an attenuation of 
      insulin-stimulated eIF4E.eIF4G association, because other stimulatory effects of 
      INS, e.g., phosphorylation of ERK1/2, 4E-BP1, S6K1, eIF4G, and eIF4E and 
      eIF4E.4E-BP1 association, were unaffected. Finally, treatment of myotubes with 
      PD-98059 or dnMEK1 adenovirus before TNF + INS addition resulted in a 
      derepression of protein synthesis and the association of eIF4G with eIF4E. These 
      findings suggest that TNF abrogates insulin-induced stimulation of protein 
      synthesis in myotubes through a decrease in eIF4F complex assembly independently 
      of S6K1 and 4E-BP1 signaling and dependently on a MEK1-sensitive signaling 
      pathway.
FAU - Williamson, David L
AU  - Williamson DL
AD  - Department of Cellular and Molecular Physiology, H166, The Pennsylvania State 
      University College of Medicine, 500 Univ. Dr., Hershey, PA 17033, USA.
FAU - Kimball, Scot R
AU  - Kimball SR
FAU - Jefferson, Leonard S
AU  - Jefferson LS
LA  - eng
GR  - DK-15658/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050208
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Drug Combinations)
RN  - 0 (Insulin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Map2k1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Drug Combinations
MH  - Insulin/*pharmacology
MH  - MAP Kinase Kinase 1/*metabolism
MH  - Mice
MH  - Muscle Fibers, Skeletal/drug effects/*metabolism
MH  - Muscle, Skeletal/drug effects/*metabolism
MH  - Protein Biosynthesis/drug effects/*physiology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2005/02/11 09:00
MHDA- 2005/07/27 09:00
CRDT- 2005/02/11 09:00
PHST- 2005/02/11 09:00 [pubmed]
PHST- 2005/07/27 09:00 [medline]
PHST- 2005/02/11 09:00 [entrez]
AID - 00397.2004 [pii]
AID - 10.1152/ajpendo.00397.2004 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2005 Jul;289(1):E95-104. doi: 
      10.1152/ajpendo.00397.2004. Epub 2005 Feb 8.