title: Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients.
abstract: BACKGROUND
  Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls.
  
  
  RESULTS
  ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.
  
  
  CONCLUSIONS
  We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.
authors.affiliation: Department of Orthopedic Surgery M, Institute of Sports Medicine Copenhagen, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. jespersen.jakob@gmail.com
authors.forename: Jakob G
authors.initials: JG
authors.lastname: Jespersen
authors.forename: Anders
authors.initials: A
authors.lastname: Nedergaard
authors.forename: Søren
authors.initials: S
authors.lastname: Reitelseder
authors.forename: Ulla R
authors.initials: UR
authors.lastname: Mikkelsen
authors.forename: Kasper J
authors.initials: KJ
authors.lastname: Dideriksen
authors.forename: Jakob
authors.initials: J
authors.lastname: Agergaard
authors.forename: Frederik
authors.initials: F
authors.lastname: Kreiner
authors.forename: Frank C
authors.initials: FC
authors.lastname: Pott
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.forename: Michael
authors.initials: M
authors.lastname: Kjaer
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D009124:Muscle Proteins