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FoxO transcription contributes to mechanical ventilation‐induced diaphragm atrophy and contractile dysfunction
Author(s) -
Smuder Ashley J,
Sollanek Kurt J,
Nelson W Bradley,
Min Kisuk,
Powers Scott K
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.939.1
Subject(s) - diaphragm (acoustics) , atrophy , microbiology and biotechnology , autophagy , skeletal muscle , weakness , muscle atrophy , medicine , biology , chemistry , endocrinology , anatomy , apoptosis , biochemistry , physics , acoustics , loudspeaker
Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in diaphragm weakness due to both muscle fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for MV‐induced diaphragm weakness is important. In this regard, activation of the FoxO family of transcription factors is reported to be necessary for disuse skeletal muscle atrophy and FoxO‐specific transcription can lead to the activation of major proteolytic systems responsible for muscle protein breakdown. Therefore, our goal was to determine the role that FoxO signaling plays in MV‐induced diaphragm atrophy. Cause and effect was determined by inhibiting the activation of FoxO though the use of a dominant negative FoxO (d.n.FoxO) adeno‐associated virus vector. Our results demonstrate that prolonged (12 hrs) MV results in a significant decrease in both diaphragm muscle fiber size and diaphragm specific force production. However, MV animals treated with d.n.FoxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting FoxO transcription attenuated the MV‐induced activation of caspase‐3, the ubiquitin‐proteasome system, and autophagy. Collectively, our findings support the hypothesis that FoxO activation plays a significant role in MV‐induced diaphragm weakness.