title: Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.
abstract: BACKGROUND
  The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.
  
  
  OBJECTIVE
  To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.
  
  
  METHODS
  In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.
  
  
  RESULTS
  Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.
  
  
  CONCLUSIONS
  GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: S A A
authors.initials: SA
authors.lastname: Bloch
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Syburra
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London, UK.
authors.forename: U
authors.initials: U
authors.lastname: Rosendahl
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London, UK Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: M J D
authors.initials: MJ
authors.lastname: Griffiths
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Kemp
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London, UK.
authors.forename: M I
authors.initials: MI
authors.lastname: Polkey
mesh_terms: D000368:Aged; D001284:Atrophy / Q000235:genetics; D002478:Cells, Cultured; D003422:Critical Care; D055515:Cysteine-Rich Protein 61 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism*; D052097:Quadriceps Muscle / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta
keywords: Not Applicable; Respiratory Muscles