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

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida; and Laboratory of Biomechanics and Physiology, Yamaguchi University, Yamaguchi, Japan

Correspondence and requests for reprints should be addressed to Scott K. Powers, Ph.D., Ed.D., Department of Applied Physiology and Kinesiology, University of Florida, Room 25, Florida Gym, Gainesville, FL 32611. E-mail: spowers{at}hhp.ufl.edu

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.

Key Words: muscle atrophy • respiratory muscle • apoptosis • ventilatory weaning

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although mechanical ventilation–induced diaphragm inactivity results in fiber atrophy, it is unknown if prolonged mechanical ventilation is associated with alterations in myonuclear domain via apoptotic mechanisms. What This Study Adds to the Field Our results reveal that inhibiting caspase-3 activation and myonuclear loss during mechanical ventilation attenuates diaphragmatic muscle atrophy.

 

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