Abstract
Autophagy promotes cancer chemotherapy‐induced oxidative stress and skeletal muscle dysfunction
The FASEB journal, Vol.32(S1), pp.856.12-856.12
04/2018
DOI: 10.1096/fasebj.2018.32.1_supplement.856.12
Abstract
Chemotherapy‐induced cachexia is a debilitating condition characterized by fatigue and muscle wasting. The onset of muscle weakness in patients often limits treatment, resulting in reduced quality of life and increased morbidity. Our previous findings show that the chemotherapeutic agent doxorubicin (DOX) causes myotoxicity as a result of reactive oxygen species (ROS) generation during intracellular metabolism of DOX by the mitochondria, and subsequent activation of the autophagy/lysosomal system. We hypothesize that DOX‐induced accelerated autophagy results in the elimination of vital cellular organelles and proteins, resulting in functional deficits to the muscle tissue. To prevent elevated activity of the autophagy/lysosomal system, we administered a dominant negative mutation of the autophagy protein ATG5 (rAAV‐dnATG5) via intramuscular injection of the rat soleus muscle four weeks prior to treatment. Animals received either DOX (20 mg/kg ip) or saline. Two days after chemotherapy, soleus muscle specific force production and fiber cross‐sectional area were significantly reduced in control animals. These changes corresponded with deficits to mitochondrial respiration, increased mitochondrial ROS emission and the increased appearance of autophagic vacuoles within the muscle. In contrast, rAAV‐dnATG5 administration in DOX treated animals prevented the conjugation of ATG12 and ATG5 thereby reducing autophagosome formation within the soleus muscle. Interestingly, the protein expression of catalase and superoxide dismutase 2 (SOD2) was elevated in these animals, which may account for improved mitochondrial respiration and reduced mitochondrial free radical production. Finally, DOX‐induced muscle fiber atrophy and contractile dysfunction were prevented in rAAV‐dnATG5 animals. These findings indicate that accelerated autophagy is an underlying cause of chemotherapy‐induced oxidative damage and skeletal muscle weakness.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Autophagy promotes cancer chemotherapy‐induced oxidative stress and skeletal muscle dysfunction
- Creators
- Ashley J. Smuder - University of South CarolinaOh Sung Kwon - University of FloridaBrian A. Hain - University of FloridaFraser E. Houston - University of FloridaErin E. Talbert - Cancer Biology and GeneticsOhio State UniversityColumbusOH
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.32(S1), pp.856.12-856.12
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2018.32.1_supplement.856.12
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Language
- English
- Date published
- 04/2018
- Academic Unit
- Health and Human Physiology; Internal Medicine; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984267154502771
Metrics
2 Record Views