title: Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes.
abstract: 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.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
authors.forename: Laura A A
authors.initials: LA
authors.lastname: Gilliam
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Moylan
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Patterson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Smith
authors.forename: Anne S
authors.initials: AS
authors.lastname: Wilson
authors.forename: Zaheen
authors.initials: Z
authors.lastname: Rabbani
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reid
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D008660:Metabolism / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D004317:Doxorubicin