Skeletal muscle wasting is a prominent feature of cancer cachexia and contributes significantly to the cancer patient’s experience of weakness and fatigue. The biology of muscle wasting involves decreased protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. Interventions that reverse this process are needed. Indomethacin has been shown to preserve skeletal muscle mass in animal models of cancer cachexia though the mechanism of action is unknown. In the present study, groups of 6 mice each, with and without tumors, were given 1 or 5 mg/kg/day indomethacin in their food. Growth of the tumor was associated with diminished gastrocnemius muscle mass. The muscles of the tumor-bearing mice had increased levels of factors associated with muscle fiber degradation: actin, ubiquitin-conjugated proteins, free ubiquitin, E3 ubiquitin ligases and the type 1 receptor for tumor necrosis factor-alpha (TNFR1). Tumor-bearing mice that were given 5 mg/kg/day, but not 1 mg/kg/day indomethacin in their food for 21 days had reduced muscle wasting and reduced levels of actin and the E3 ligases in their muscles. Both 5 and 1 mg/kg/day indomethacin significantly reduced levels of TNFR1, while neither dose affected levels of free ubiquitin. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins in the muscles of both tumor-bearing and healthy control animals, suggesting it may function as an inhibitor of proteasome activity. These data suggest that the beneficial effects of indomethacin in this animal model of cancer cachexia may involve inhibition of TNF and ubiquitin-mediated pathways of skeletal muscle wasting. Further studies of the effects of anti-inflammatory drugs in other animal models of cancer cachexia are needed before undertaking clinical trials in cancer patients.
Session #1185 - Oncology Nursing Research
The 29th Annual MNRS Research Conference (April 1-4, 2005)