title: Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients.
abstract: BACKGROUND
  The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.
  
  
  OBJECTIVE
  We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.
  
  
  METHODS
  We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.
  
  
  RESULTS
  Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.
  
  
  CONCLUSIONS
  These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
authors.affiliation: 1 Department of Physiology.
authors.forename: Pleuni E
authors.initials: PE
authors.lastname: Hooijman
authors.forename: Albertus
authors.initials: A
authors.lastname: Beishuizen
authors.forename: Christian C
authors.initials: CC
authors.lastname: Witt
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Armand R J
authors.initials: AR
authors.lastname: Girbes
authors.forename: Angelique M E
authors.initials: AM
authors.lastname: Spoelstra-de Man
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Emmy
authors.initials: E
authors.lastname: Manders
authors.forename: Hieronymus W H
authors.initials: HW
authors.lastname: van Hees
authors.forename: Charissa E
authors.initials: CE
authors.lastname: van den Brom
authors.forename: Vera
authors.initials: V
authors.lastname: Silderhuis
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Hartemink
authors.forename: Marinus A
authors.initials: MA
authors.lastname: Paul
authors.forename: Leo M A
authors.initials: LM
authors.lastname: Heunks
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D016022:Case-Control Studies; D016638:Critical Illness; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins; D018908:Muscle Weakness / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D009426:Netherlands; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects*; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: diaphragm weakness; mechanical ventilation; single muscle fiber; weaning failure