Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction.
OBJECTIVE
Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown.


METHODS
This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness.


METHODS
University research laboratory.


METHODS
Young adult female Sprague-Dawley rats.


METHODS
Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm.


RESULTS
Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3.


CONCLUSIONS
Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.
1Department of Applied Physiology and Kinesiology Center for Exercise Science, University of Florida, Gainesville, FL. 2Department of Pharmacology, Yale University, New Haven, CT. 3Division of Mathematics, Computer and Natural Sciences, Ohio Dominican University, Columbus, OH.
Ashley J
AJ
Smuder
Kurt J
KJ
Sollanek
Kisuk
K
Min
W Bradley
WB
Nelson
Scott K
SK
Powers
D000818:Animals; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D006439:Hemodynamics; D009119:Muscle Contraction; D009133:Muscular Atrophy; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1