title: Novel events in the molecular regulation of muscle mass in critically ill patients.
abstract: Critically ill patients experience marked skeletal muscle atrophy, but the molecular mechanisms responsible for this are largely unresolved. Therefore, we investigated key genes and proteins, identified from cell and animal studies to control protein synthesis and breakdown, in vastus lateralis biopsy samples obtained from 10 patients and 10 age- and sex-matched healthy controls. Muscle cytokines IL-6 and TNF-α mRNA were higher in patients than in controls(6.5-fold; P < 0.001 and 2-fold; P < 0.01). From the perspective of muscle protein breakdown, muscle-specific E3-ligases (MAFbx and MuRF1) were higher in patients at mRNA (4.5-fold; P < 0.05 and 2.5-fold; P < 0.05) and protein (5-fold; P < 0.001 and 4.5-fold; P < 0.001) level. Furthermore, 20S proteasome mRNA and protein were higher in patients (5-fold; P < 0.001 and 2.5-fold; P < 0.01). Cathepsin-L mRNA was 2-fold higher (P < 0.01), whilst calpain-3 mRNA(2-fold; P < 0.01) and protein (4-fold; P < 0.01)were lower inpatients. Another novel observation was the 3-fold (P < 0.05) and 8.5-fold (P < 0.001) higher expression of myostatin mRNA and protein in patients. Widespread dephosphorylation (inactivation) of proteins regulating translation initiation factor activation and protein synthesis (Akt1, GSK3α,β, mTOR, p70S6K and 4E-BP1) was observed in patients, which was paralleled by increases in their mRNAs. Finally, PDK4 mRNA and protein was 2-fold (P < 0.05) and 2.6-fold (P < 0.01), respectively, higher inpatients. In conclusion, we showed comprehensive alterations in molecular events thought to reduce muscle mass and carbohydrate (CHO) oxidation in critically ill patients. Nevertheless,these catabolic events were matched by a cellular programme of anabolic restoration at the transcriptional level. This shows a high molecular plasticity in the muscle of patients, and strategies to preserve muscle mass and metabolic function should focus on maintaining Akt phosphorylation and inhibiting myostatin expression.C
authors.affiliation: School of Biomedical Sciences, Nottingham University Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. despina.constantin@nottingham.ac.uk
authors.forename: Despina
authors.initials: D
authors.lastname: Constantin
authors.forename: Justine
authors.initials: J
authors.lastname: McCullough
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Mahajan
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000502:physiology; D002403:Cathepsins / Q000378:metabolism; D016638:Critical Illness; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational / Q000235:genetics / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D039642:Eukaryotic Initiation Factors; D015850:Interleukin-6; D009124:Muscle Proteins; D055435:Myostatin; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D002403:Cathepsins; D046988:Proteasome Endopeptidase Complex