Activated Protein Synthesis and Suppressed Protein Breakdown Signaling in Skeletal Muscle of Critically Ill Patients

作者：Jespersen Jakob G^*; Nedergaard Anders; Reitelseder Soren; Mikkelsen Ulla R; Dideriksen Kasper J; Agergaard Jakob; Kreiner Frederik; Pott Frank C; Schjerling Peter; Kjaer Michael

来源：PLos One, 2011, 6(3): e18090.

DOI：10.1371/journal.pone.0018090

Background: Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3 beta (GSK3 beta) 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.
Methodology/Principal Findings: 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, GSK3 beta, 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 alpha (TNF-alpha) 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 (r(2) = 0.36, p < 0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.
Conclusions/Significance: 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.

• 出版日期2011-3-31