Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes

Laura A.A. Gilliam, Jennifer S. Moylan, Elaine W. Patterson, Jeffrey D. Smith, Anne S. Wilson, Zaheen Rabbani, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


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.

Original languageEnglish
Pages (from-to)C195-C202
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1
StatePublished - Jan 2012


  • Cancer cachexia
  • Oxidative stress
  • Reactive oxygen species
  • Skeletal muscle

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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