PMID- 17505052
OWN - NLM
STAT- MEDLINE
DCOM- 20070924
LR  - 20211203
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 293
IP  - 2
DP  - 2007 Aug
TI  - Regulation of muscle protein synthesis during sepsis and inflammation.
PG  - E453-9
AB  - Prolonged sepsis and exposure to an inflammatory milieu decreases muscle protein 
      synthesis and reduces muscle mass. As a result of its ability to integrate 
      diverse signals, including hormones and nutrients, the mammalian target of 
      rapamycin (mTOR) is a dominant regulator in the translational control of protein 
      synthesis. Under postabsorptive conditions, sepsis decreases mTOR kinase activity 
      in muscle, as evidenced by reduced phosphorylation of both eukaryotic initiation 
      factor (eIF)4E-binding protein (BP)-1 and ribosomal S6 kinase (S6K)1. These 
      sepsis-induced changes, along with the redistribution of eIF4E from the active 
      eIF4E.eIF4G complex to the inactive eIF4E.4E-BP1 complex, are preventable by 
      neutralization of tumor necrosis factor (TNF)-alpha but not by antagonizing 
      glucocorticoid action. Although the ability of mTOR to respond to insulin-like 
      growth factor (IGF)-I is not disrupted by sepsis, the ability of leucine to 
      increase 4E-BP1 and S6K1 phosphorylation is greatly attenuated. This "leucine 
      resistance" results from a cooperative interaction between both TNF-alpha and 
      glucocorticoids. Finally, although septic animals are not IGF-I resistant, the 
      anabolic actions of IGF-I are nonetheless reduced because of the development of 
      growth hormone resistance, which decreases both circulating and muscle IGF-I. 
      Herein, we highlight recent advances in the mTOR signaling network and emphasize 
      their connection to the atrophic response observed in skeletal muscle during 
      sepsis. Although many unanswered questions remain, understanding the cellular 
      basis of the sepsis-induced decrease in translational activity will contribute to 
      the rational development of therapeutic interventions and thereby minimize the 
      debilitating affects of the atrophic response that impairs patient recovery.
FAU - Lang, Charles H
AU  - Lang CH
AD  - Department of Cellular and Molecular Physiology, The Pennsylvania State 
      University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
FAU - Frost, Robert A
AU  - Frost RA
FAU - Vary, Thomas C
AU  - Vary TC
LA  - eng
GR  - GM-38032/GM/NIGMS NIH HHS/United States
GR  - GM-39277/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20070515
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Amino Acids)
RN  - 0 (Muscle Proteins)
RN  - 0 (Peptide Initiation Factors)
RN  - 0 (RNA Cap-Binding Proteins)
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acids/physiology
MH  - Animals
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Inflammation/*genetics/metabolism
MH  - Metabolic Networks and Pathways/physiology
MH  - Models, Biological
MH  - Muscle Proteins/*genetics/metabolism
MH  - Nutritional Physiological Phenomena
MH  - Peptide Initiation Factors/physiology
MH  - Protein Biosynthesis/*physiology
MH  - Protein Kinases/physiology
MH  - RNA Cap-Binding Proteins/metabolism/physiology
MH  - Ribosomal Protein S6/metabolism
MH  - Sepsis/*genetics/metabolism
MH  - TOR Serine-Threonine Kinases
RF  - 62
EDAT- 2007/05/17 09:00
MHDA- 2007/09/25 09:00
CRDT- 2007/05/17 09:00
PHST- 2007/05/17 09:00 [pubmed]
PHST- 2007/09/25 09:00 [medline]
PHST- 2007/05/17 09:00 [entrez]
AID - 00204.2007 [pii]
AID - 10.1152/ajpendo.00204.2007 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E453-9. doi: 
      10.1152/ajpendo.00204.2007. Epub 2007 May 15.