Mechanism of muscle protein degradation in cancer cachexia.

Kl Smith,Mj Tisdale

doi:10.1038/bjc.1993.334

Abstract

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.

Highlights

Animals Pure strain female NMRI mice were obtained from our own breeding colony and were fed a rat and mouse breeding diet (Pilsbury Ltd., Birmingham, UK) and water ad libitum
We have previously shown that loss of skeletal muscle protein in mice bearing the MAC16 adenocarcinoma arises from a depression of protein synthesis accompanied by a massive increase in protein degradation, which increases with increasing weight loss (Beck et al, 1991)
We have recently reported that eicosapentaenoic acid (EPA) is an effective inhibitor of the weight loss in animals bearing MAC16 tumour (Beck et al, 1991)

Summary

Introduction

Animals Pure strain female NMRI mice were obtained from our own breeding colony and were fed a rat and mouse breeding diet (Pilsbury Ltd., Birmingham, UK) and water ad libitum. Animals (average body weight 20 g) were transplanted with fragments of the MAC16 tumour into the flank by means of a trocar as previously described (Bibby et al, 1987). Weight loss started to occur 10 to 12 days after transplantation when the tumours became palpable and animals were used with varying degrees of weight loss up to a maximum of 25 to 30% as agreed by the Coordinating Committee on Cancer Research of the United Kingdom for the welfare of animals with neoplasms. Blood was removed from animals by cardiac puncture under anesthesia using a mixture of halothane, oxygen and nitrous oxide between 9.30 and 10.30a.m. Blood samples were allowed to clot for 10 min at room temperature and serum was produced by centrifugation at 13,000 rpm for 5 min an a microfuge.

Methods

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Discussion

Conclusion