Journal article
Crosstalk between autophagy and oxidative stress regulates proteolysis in the diaphragm during mechanical ventilation
Free radical biology & medicine, Vol.115, pp.179-190
11/29/2017
DOI: 10.1016/j.freeradbiomed.2017.11.025
PMCID: PMC5767544
PMID: 29197632
Abstract
Mechanical ventilation (MV) results in the rapid development of ventilator-induced diaphragm dysfunction (VIDD). While the mechanisms responsible for VIDD are not fully understood, recent data reveal that prolonged MV activates autophagy in the diaphragm, which may occur as a result of increased cellular reactive oxygen species (ROS) production. Therefore, we tested the hypothesis that 1) accelerated autophagy is a key contributor to VIDD; and that 2) oxidative stress is required to increase the expression of autophagy genes in the diaphragm. Our findings reveal that targeted inhibition of autophagy in the rat diaphragm prevented MV-induced muscle atrophy and contractile dysfunction. Attenuation of VIDD in these animals occurred as a result of increased diaphragm concentration of the antioxidant catalase and reduced mitochondrial ROS emission, which corresponded to reductions in the activity of calpain and caspase-3. To determine if increased ROS production is required for the upregulation of autophagy biomarkers in the diaphragm, rats that were administered the mitochondrial-targeted peptide SS-31 during MV. Results from this study demonstrated that mitochondrial ROS production in the diaphragm during MV is required for the increased expression of key autophagy genes (i.e. LC3, ATG7, ATG12, Beclin1 and p62), as well as for increased activity of cathepsin L. Together, these data reveal that autophagy is required for VIDD, and that autophagy inhibition reduces MV-induced diaphragm ROS production and prevents a positive feedback loop whereby increased autophagy is stimulated by oxidative stress, resulting in further increases in ROS and autophagy.
Details
- Title: Subtitle
- Crosstalk between autophagy and oxidative stress regulates proteolysis in the diaphragm during mechanical ventilation
- Creators
- Ashley J Smuder - University of South CarolinaKurt J Sollanek - Sonoma State UniversityW. Bradley Nelson - Ohio Dominican UniversityKisuk Min - Yale UniversityErin E Talbert - The Ohio State UniversityAndreas N Kavazis - University of MichiganMatthew B Hudson - University of DelawareMarco Sandri - University of PaduaHazel H Szeto - Cornell UniversityScott K Powers - University of Florida
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.115, pp.179-190
- DOI
- 10.1016/j.freeradbiomed.2017.11.025
- PMID
- 29197632
- PMCID
- PMC5767544
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R21AR064956
- Language
- English
- Date published
- 11/29/2017
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984259645402771
Metrics
15 Record Views