Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 585, Issue 1, Pages 203-215Publisher
BLACKWELL PUBLISHING
DOI: 10.1113/jphysiol.2007.141119
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Funding
- NHLBI NIH HHS [R01 HL072789] Funding Source: Medline
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Oxidative stress promotes controlled mechanical ventilation (MV)-induced diaphragmatic atrophy. Nonetheless, the signalling pathways responsible for oxidative stress-induced muscle atrophy remain unknown. We tested the hypothesis that oxidative stress down-regulates insulin-like growth factor-1-phosphotidylinositol 3-kinase-protein kinase B serine threonine kinase (IGF-1-PI3K-Akt) signalling and activates the forkhead box O (FoxO)class of transcription factors in diaphragm fibres during MV-induced diaphragm inactivity. Sprague - Dawley rats were randomly assigned to one of five experimental groups: ( 1) control ( Con), ( 2) 6 h of MV, ( 3) 6 h of MV with infusion of the antioxidant Trolox, ( 4) 18 h of MV, ( 5) 18 h of MV with Trolox. Following 6 h and 18 h of MV, diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4, culminating in increased expression of the muscle-specific ubiquitin ligases, muscle atrophy factor ( MAFbx) and muscle ring finger-1 (MuRF-1). Interestingly, following 18 h of MV, antioxidant administration was associated with attenuation of MV-induced atrophy in type I, type IIa and type IIb/IIx myofibres. Collectively, these data reveal that the antioxidant Trolox attenuates MV-induced diaphragmatic atrophy independent of alterations in Akt regulation of FoxO transcription factors and expression of MAFbx or MuRF-1. Further, these results also indicate that differential regulation of diaphragmatic IGF-1-PI3K-Akt signalling exists during the early and late stages of MV.
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