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Published ahead of print on November 2, 2006, doi:10.1164/rccm.200601-142OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 2, January 2007, 150-159

A more recent version of this article appeared on January 15, 2007
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Submitted on January 31, 2006
Accepted on October 27, 2006

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation-Induced Atrophy

Joseph M McClung1, Andreas N Kavazis1, Keith C DeRuisseau1, Darin J Falk1, Melissa A Deering1, Youngil Lee1, Takao Sugiura2, and Scott K Powers1*

1 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA, 2 Laboratory of Biomechanics and Physiology, Yamaguchi University, Yamaguchi, Japan

* To whom correspondence should be addressed. E-mail: spowers{at}hhp.ufl.edu.

Rationale: Unloading the diaphragm via mechanical ventilation results in rapid diaphragmatic fiber atrophy. However, it is currently unknown whether the myonuclear domain (cytoplasmic myofiber volume/myonucleus) of diaphragm myofibers is altered during mechanical ventilation. Objective: We tested the hypothesis that mechanical ventilation-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 either a control or experimental groups exposed to 6- or 12-hours of mechanical ventilation with or without administration of a caspase-3 inhibitor. Measurements and Main Results: Following 12-hours of mechanical ventilation, 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 also decreased after 12-hours of mechanical ventilation and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6- and 12-hours of mechanical ventilation 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). Interestingly, caspase-3 dependent increases in apoptotic markers occurred following 6-hours of mechanical ventilation, prior to the onset of myofiber atrophy. Conclusions: Collectively, these data support the ypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged mechanical ventilation and that caspase-3-mediated myonuclear apoptosis contributes to this process.
Key words: muscle atrophy, respiratory muscle, apoptosis, ventilatory weaning




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