Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients

• Published in: PloS one 2011-03, Vol.6 (3), p.e18090-e18090
• Main Authors: Jespersen, Jakob G, Nedergaard, Anders, Reitelseder, Søren, Mikkelsen, Ulla R, Dideriksen, Kasper J, Agergaard, Jakob, Kreiner, Frederik, Pott, Frank C, Schjerling, Peter, Kjaer, Michael
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aging; AKT protein; Alcohol; Amino acids; Biology; Blotting, Western; Bone surgery; Branched chain amino acids; Breakdown; Care and treatment; Case-Control Studies; Cell cycle; Chain branching; Comparative analysis; Critical Illness; Diabetes; Diabetes therapy; Dietary fiber; Electrolytes; Female; Forkhead protein; FOXO1 protein; FOXO3 protein; Gene expression; Glucose; Glycogen; Glycogen synthase kinase 3; Glycogen synthesis; Hospital patients; Hospitals; Humans; Illnesses; Inflammation; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Interleukin; Interleukin 6; Interleukins; Kinases; Male; Medicine; Metabolism; Middle Aged; Mortality; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Myostatin; Orthopedics; Pathways; Patients; Phosphates; Phosphorylation; Polymerase chain reaction; Protein binding; Protein Biosynthesis; Protein synthesis; Protein turnover; Proteins; Proteolysis; Rapamycin; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal protein S6; Ribosomal protein S6 kinase; RNA; Rodents; Sepsis; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Skeletal muscle; Thigh; TOR protein; Translation (Genetics); Type 2 diabetes; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018090

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. 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