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

Joseph M. McClung, Andreas N. Kavazis, Keith C. DeRuisseau, Darin J. Falk, Melissa A. Deering, Youngil Lee, Takao Sugiura, Scott K. Powers

Research output: Contribution to journalArticle

129 Scopus citations

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:Wetested 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.

Original languageEnglish (US)
Pages (from-to)150-159
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume175
Issue number2
DOIs
StatePublished - Jan 23 2007

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Keywords

  • Apoptosis
  • Muscle atrophy
  • Respiratory muscle
  • Ventilatory weaning

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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