title: Inhibition of the ubiquitin-proteasome pathway does not protect against ventilator-induced accelerated proteolysis or atrophy in the diaphragm.
abstract: BACKGROUND
  Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD.
  
  
  METHODS
  The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group).
  
  
  RESULTS
  The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx.
  
  
  CONCLUSIONS
  Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.
authors.affiliation: From the Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida (A.J.S., S.K.P.); Division of Mathematics, Computer, and Natural Sciences, Department of Natural Sciences, Ohio Dominican University, Columbus, Ohio (W.B.N.); Department of Medicine, Emory University, Atlanta, Georgia (M.B.H.); and School of Kinesiology, Auburn University, Auburn, Alabama (A.N.K.).
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.forename: W Bradley
authors.initials: WB
authors.lastname: Nelson
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hudson
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kavazis
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000758:Anesthesia; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001284:Atrophy; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis; D003964:Diaphragm / Q000473:pathology*; D005260:Female; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012121:Respiration, Artificial; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000903:Antibiotics, Antineoplastic; D001897:Boronic Acids; D018076:DNA, Complementary; D009124:Muscle Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D011719:Pyrazines; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D000069286:Bortezomib; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin