Abstract
BackgroundSkeletal 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.Methodology/Principal FindingsICU 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/SignificanceWe 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.
Highlights
Skeletal muscle, which constitutes 30–40% of human body weight [1], is critical for numerous functions such as breathing, locomotion and metabolism, and this most abundant tissue serves as a large protein reservoir
Akt is activated by insulin and insulin-like growth factor 1 (IGF-1) and has two known major downstream branches relevant to muscle protein synthesis: the mammalian target of rapamycin (mTOR) pathway, which is activated by Akt, and the glycogen synthase kinase 3b (GSK3b) pathway, which is inhibited by Akt. mTOR seems to be a key regulator of cell size and protein synthesis combining signals from growth factors and nutrients [9,11]. mTOR is comprised of complex1 and 2, and the effect of mTOR on protein synthesis is mediated through mTORC1 by the activation of S6 kinase (S6k) and the inhibition of 4E binding protein 1 (4E-BP1)
In our fed intensive care unit (ICU) patients compared with post-absorptive controls we observe a very similar pattern of differences in plasma amino acid concentrations including lower leucine levels in patients (Table 4) as shown previously in post-absorptive septic patients compared with healthy controls [42]
Summary
Skeletal muscle, which constitutes 30–40% of human body weight [1], is critical for numerous functions such as breathing, locomotion and metabolism, and this most abundant tissue serves as a large protein reservoir. Akt (aka protein kinase B) is activated by insulin and IGF-1 and has two known major downstream branches relevant to muscle protein synthesis: the mTOR pathway, which is activated by Akt, and the GSK3b pathway, which is inhibited by Akt. mTOR seems to be a key regulator of cell size and protein synthesis combining signals from growth factors and nutrients [9,11]. Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3b (GSK3b) 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
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