title: Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.
abstract: BACKGROUND
  Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important.
  
  
  OBJECTIVE
  These experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm.
  
  
  METHODS
  Cause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31).
  
  
  METHODS
  None.
  
  
  RESULTS
  Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction.
  
  
  CONCLUSIONS
  These results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced diaphragmatic weakness.
authors: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA. spowers@hhp.ufl.edu
authors: Scott K
authors: SK
authors: Powers
authors: Matthew B
authors: MB
authors: Hudson
authors: W Bradley
authors: WB
authors: Nelson
authors: Erin E
authors: EE
authors: Talbert
authors: Kisuk
authors: K
authors: Min
authors: Hazel H
authors: HH
authors: Szeto
authors: Andreas N
authors: AN
authors: Kavazis
authors: Ashley J
authors: AJ
authors: Smuder
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D009133:Muscular Atrophy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000199:Actins; D009124:Muscle Proteins; D009842:Oligopeptides; D000070584:Tripartite Motif Proteins; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D006861:Hydrogen Peroxide; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D002154:Calpain; D053148:Caspase 3