Indomethacin preserves muscle mass and reduces levels of E3 ligases and TNF receptor type 1 in the gastrocnemius muscle of tumor-bearing mice.
Tumor-induced skeletal muscle wasting involves tumor necrosis factor (TNF) and the ubiquitin-proteasome pathway of muscle protein degradation. In this study, growth of the colon-26 adenocarcinoma in mice was associated with diminished gastrocnemius muscle mass and increased muscle levels of actin, ubiquitin-conjugated proteins, free ubiquitin, E3 ubiquitin ligases, and the type 1 TNF receptor (TNFR1). Indomethacin at 1 or 5 mg/kg/day reduced tumor growth and muscle levels of TNFR1. However, only the 5 mg dose of indomethacin reduced muscle wasting and muscle levels of the E3 ligases and actin. These data suggest that the beneficial effects of indomethacin in the treatment of tumor-induced skeletal muscle wasting may involve inhibition of TNF- and ubiquitin-mediated pathways of muscle protein degradation. These data also demonstrate that E3 ligases, which are involved in disuse atrophy, also are associated with tumor-induced skeletal muscle wasting.
Hitt
Andrew
A
National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA.
Graves
Erin
E
McCarthy
Donna O
DO
D000230:Adenocarcinoma / Q000150:complications / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D003110:Colonic Neoplasms / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000150:complications / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D007213:Indomethacin