RESUMO
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.
Assuntos
Doxorrubicina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular , Humanos , Metabolismo/efeitos dos fármacos , Metabolismo/fisiologia , Fibras Musculares Esqueléticas/citologiaRESUMO
The Achilles tendon of the patient with Charcot's foot neuroarthropathy has significantly altered physical properties compared with a normal tendon. Twenty-nine Achilles tendons from patients with Charcot's foot (n = 20) and non-Charcot's foot controls (n = 9) were loaded onto a biomechanical testing instrument. The biomechanical properties of the Charcot and control tendons were determined and the tendons were evaluated for differences in ultimate tensile strength and elasticity (Young's modulus). Biomechanical test data show that there is a significant difference in ultimate tensile strength and elasticity between tendons of patients with Charcot's foot and those of non-Charcot's controls. The term diabetic tendo Achillis equinus is introduced as a new finding in diabetic neuroarthropathy.
