title: Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation.
abstract: BACKGROUND
  Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is poorly understood.
  
  
  OBJECTIVE
  To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, and the role of mitochondria-derived oxidative stress in the development of VIDD.
  
  
  METHODS
  Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 h) and age-matched control subjects were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene and protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions.
  
  
  RESULTS
  In human MV diaphragms, mitochondrial biogenesis and content were down-regulated, with a more specific defect of respiratory chain cytochrome-c oxidase. Laser capture microdissection of cytochrome-c oxidase-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins) were consistent with energy substrate excess as a possible stimulus for these changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3) was protective against VIDD.
  
  
  CONCLUSIONS
  Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility that develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process.
authors.affiliation: Meakins-Christie Laboratories, 3626 Saint Urbain Street, Montreal, PQ, H2X 2P2 Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.forename: Ilan
authors.initials: I
authors.lastname: Azuelos
authors.forename: Sabah
authors.initials: S
authors.lastname: Hussain
authors.forename: Peter
authors.initials: P
authors.lastname: Goldberg
authors.forename: Richard
authors.initials: R
authors.lastname: Godin
authors.forename: Gawiyou
authors.initials: G
authors.lastname: Danialou
authors.forename: Rakesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Karolina
authors.initials: K
authors.lastname: Rygiel
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: George
authors.initials: G
authors.lastname: Karpati
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.forename: Yan
authors.initials: Y
authors.lastname: Burelle
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Tanja
authors.initials: T
authors.lastname: Taivassalo
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D003964:Diaphragm / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D063306:Mitophagy; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012121:Respiration, Artificial / Q000009:adverse effects*; D018709:Statistics, Nonparametric; D046509:Tissue Culture Techniques