Mechanical Ventilation–induced Diaphragm Disuse in Humans Triggers Autophagy
- 1 December 2010
- journal article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 182 (11), 1377-1386
- https://doi.org/10.1164/rccm.201002-0234oc
Abstract
Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.Keywords
This publication has 55 references indexed in Scilit:
- p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wastingAmerican Journal of Physiology-Cell Physiology, 2010
- Regulation Mechanisms and Signaling Pathways of AutophagyAnnual Review of Genetics, 2009
- FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent mannerAmerican Journal of Physiology-Cell Physiology, 2009
- Apocynin attenuates diaphragm oxidative stress and protease activation during prolonged mechanical ventilationCritical Care Medicine, 2009
- Antioxidant administration attenuates mechanical ventilation‐induced rat diaphragm muscle atrophy independent of protein kinase B (PKB–Akt) signallingThe Journal of Physiology, 2007
- Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced AtrophyAmerican Journal of Respiratory and Critical Care Medicine, 2007
- PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcriptionProceedings of the National Academy of Sciences of the United States of America, 2006
- The Role of Cytokines during the Pathogenesis of Ventilator-Associated and Ventilator-Induced Lung InjurySeminars in Respiratory and Critical Care Medicine, 2006
- Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragmJournal of Applied Physiology, 2005
- Abnormalities of diaphragmatic muscle in neonates with ventilated lungsThe Journal of Pediatrics, 1988