title: Caspase-3 regulation of diaphragm myonuclear domain during mechanical ventilation-induced atrophy.
abstract: BACKGROUND
  Unloading the diaphragm via mechanical ventilation (MV) results in rapid diaphragmatic fiber atrophy. It is unknown whether the myonuclear domain (cytoplasmic myofiber volume/myonucleus) of diaphragm myofibers is altered during MV.
  
  
  OBJECTIVE
  We tested the hypothesis that MV-induced diaphragmatic atrophy is associated with a loss of myonuclei via a caspase-3-mediated, apoptotic-like mechanism resulting in a constant myonuclear domain.
  
  
  METHODS
  To test this postulate, Sprague-Dawley rats were randomly assigned to a control group or to experimental groups exposed to 6 or 12 h of MV with or without administration of a caspase-3 inhibitor.
  
  
  RESULTS
  After 12 h of MV, type I and type IIa diaphragm myofiber areas were decreased by 17 and 23%, respectively, and caspase-3 inhibition attenuated this decrease. Diaphragmatic myonuclear content decreased after 12 h of MV and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6 and 12 h of MV resulted in caspase-3-dependent increases in apoptotic markers in the diaphragm (e.g., number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei and DNA fragmentation). Caspase-3-dependent increases in apoptotic markers occurred after 6 h of MV, before the onset of myofiber atrophy.
  
  
  CONCLUSIONS
  Collectively, these data support the hypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged MV and that caspase-3-mediated myonuclear apoptosis contributes to this process.
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Room 25, Florida Gym, Gainesville, FL 32611, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McClung
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kavazis
authors.forename: Keith C
authors.initials: KC
authors.lastname: DeRuisseau
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Deering
authors.forename: Youngil
authors.initials: Y
authors.lastname: Lee
authors.forename: Takao
authors.initials: T
authors.lastname: Sugiura
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D017209:Apoptosis; D001284:Atrophy / Q000201:enzymology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism*; D003964:Diaphragm / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D053148:Caspase 3