Mechanism of muscle protein degradation in cancer cachexia.
Depletion of skeletal muscle mass in animals bearing an experimental model of cachexia, the MAC16 adenocarcinoma, occurs by a reduction in protein synthesis accompanied by a large increase in protein degradation. Serum from mice bearing the MAC16 tumour produced an increased protein degradation in isolated gastrocnemius muscle, as measured by tyrosine release, with a maximal effect occurring with serum from animals with a weight loss of between 11 and 20%. The response was specific to the cachectic state, since serum from mice bearing the MAC13 adenocarcinoma, which does not produce weight loss, did not increase tyrosine release from gastrocnemius muscle above that observed with serum from non tumour-bearing animals. The circulatory proteolysis-inducing factor was stable to heating at 60 degrees C for 5 min and was not inhibited by phenylmethylsulfonyl fluoride, suggesting that it was not a serine protease. The level of prostaglandin E2 (PGE2) in gastrocnemius muscle was significantly elevated after incubation with serum from cachectic mice bearing the MAC16 tumour. Both indomethacin and the polyunsaturated fatty acid eicosapentaenoic acid (EPA) inhibited the rise in muscle PGE2 content in response to serum from cachectic mice and also inhibited muscle protein degradation. These results suggest that muscle protein degradation in cancer cachexia is associated with a rise in PGE2 content.
Smith
K L
KL
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Tisdale
M J
MJ
D000230:Adenocarcinoma / Q000097:blood / Q000503:physiopathology*; D000818:Animals; D002100:Cachexia / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009124:Muscle Proteins / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values
D009124:Muscle Proteins; D015118:Eicosapentaenoic Acid; D015232:Dinoprostone; D007213:Indomethacin