Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes

Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing treatment and increases mitochondrial reactive oxygen species (ROS) production. ROS stimulate protein degradation in muscle by activating proteolytic systems that include caspase-3...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2012-01, Vol.302 (1), p.C195-C202
Main Authors: Gilliam, Laura A A, Moylan, Jennifer S, Patterson, Elaine W, Smith, Jeffrey D, Wilson, Anne S, Rabbani, Zaheen, Reid, Michael B
Format: Article
Language:English
Subjects:
Cancer
Cell Differentiation - drug effects
Cell Differentiation - physiology
Cell Line
Doxorubicin - pharmacology
Humans
Medical treatment
Metabolism - drug effects
Metabolism - physiology
Mitochondria - drug effects
Mitochondria - metabolism
Muscle Cell Biology and Cell Motility
Muscle Fibers, Skeletal - cytology
Muscle Fibers, Skeletal - drug effects
Muscle Fibers, Skeletal - metabolism
Musculoskeletal system
Oxidation
Proteins
Reactive Oxygen Species - metabolism
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Summary:Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing treatment and increases mitochondrial reactive oxygen species (ROS) production. ROS stimulate protein degradation in muscle by activating proteolytic systems that include caspase-3 and the ubiquitin-proteasome pathway. We hypothesized that doxorubicin causes skeletal muscle catabolism through ROS, causing upregulation of E3 ubiquitin ligases and caspase-3. We tested this hypothesis by exposing differentiated C2C12 myotubes to doxorubicin (0.2 μM). Doxorubicin decreased myotube width 48 h following exposure, along with a 40-50% reduction in myosin and sarcomeric actin. Cytosolic oxidant activity was elevated in myotubes 2 h following doxorubicin exposure. This increase in oxidants was followed by an increase in the E3 ubiquitin ligase atrogin-1/muscle atrophy F-box (MAFbx) and caspase-3. Treating myotubes with SS31 (opposes mitochondrial ROS) inhibited expression of ROS-sensitive atrogin-1/MAFbx and protected against doxorubicin-stimulated catabolism. These findings suggest doxorubicin acts via mitochondrial ROS to stimulate myotube atrophy.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00217.2011