Mechanical Ventilation-Induced Alterations in Diaphragmatic Akt Signalling and FOXO Activation

Abstract

PURPOSE: Mechanical ventilation (MV) unloads the diaphragm and results in the rapid onset of diaphragmatic oxidative stress, contractile dysfunction, proteolysis, and myofiber atrophy. We tested the hypothesis that prolonged MV would alter diaphragmatic protein kinase B (Akt) signalling to the forkhead box (FOXO) family of transcription factors. METHODS: To test this postulate, Sprague-Dawley rats were randomly assigned to one of three experimental groups: control, 6-hour MV, and 18-hour MV. RESULTS: 18-hours of MV decreased diaphragmatic Type I, Type IIa, and Type IIx/IIb myofiber cross sectional areas. Prolonged MV (18hr) decreased cytosolic Akt activity (−37%) in the diaphragm and coincided with increased activation of 4E-BP1 and decreased activation of p70s6kinase protein. Further, phosphorylation of diaphragmatic cytosolic FOXO1 decreased 25% and 30% with 6-and 18-hours of MV, respectively. Finally, nuclear FOXO1 protein abundance increased 30-40% with 6-and 18-hours of MV and coincided with increased FOXO1 transcriptional activation at both time-points. CONCLUSIONS: Collectively, these data are consistent with the concept that MV-induced Akt-FOXO signalling contributes to MV-induced diaphragmatic myofiber atrophy. This work was supported by National Institutes of Health (R01 HL072789).