Caspase-3 regulation of diaphragm myonuclear domain during mechanical ventilation-induced atrophy

Am J Respir Crit Care Med. 2007 Jan 15;175(2):150-9. doi: 10.1164/rccm.200601-142OC. Epub 2006 Nov 2.

Abstract

Rationale: 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.

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Atrophy / enzymology
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Caspase 3 / analysis
  • Caspase 3 / metabolism*
  • Diaphragm / enzymology*
  • Diaphragm / pathology*
  • Female
  • Rats
  • Rats, Sprague-Dawley
  • Respiration, Artificial / adverse effects*

Substances

  • Biomarkers
  • Caspase 3