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Chemotherapy Inhibits Skeletal Muscle Ubiquitin-Proteasome-dependent Proteolysis¹

Human Nutrition Research Center, Nutrition and Protein Metabolism Unit, Institut National de la Recherche Agronomique de Theix, 63122 Ceyrat, France [T. T., S. T., L. C., D. T., M-N. P., M. C., D. A.]; Laboratoire de Biologie de la Nutrition, Faculté de Pharmacie, Université Paris V, 75270 Paris Cedex 06, France [D. M. C., T. L. B.]; Food, Nutrition and Health, Faculty of Agricultural Sciences, The University of British Columbia, Vancouver, British Columbia, V6T 1Z4 Canada [S. E. S.]; and Institut National de la Santé et de la Recherche Médicale UMR 484, 63005 Clermont-Ferrand Cedex, France [E. D., J-C. M.]

Chemotherapy has cachectic effects, but it is unknown whether cytostatic agents alter skeletalmuscle proteolysis. We hypothesized that chemotherapy-induced alterations in protein synthesis should result in the increased incidence of abnormal proteins, which in turn should stimulate ubiquitin-proteasome-dependent proteolysis. The effects of the nitrosourea cystemustine were investigated in skeletal muscles from both healthy and colon 26 adenocarcinoma-bearing mice, an appropriate model for testing the impact of cytostatic agents. Muscle wasting was seen in both groups of mice 4 days after a single cystemustine injection, and the drug further increased the loss of muscle proteins already apparent in tumor-bearing animals. Cystemustine cured the tumor-bearing mice with 100% efficacy. Surprisingly, within 11 days of treatment, rates of muscle proteolysis progressively decreased below basal levels observed in healthy control mice and contributed to the cessation of muscle wasting. Proteasome-dependent proteolysis was inhibited by mechanisms that include reduced mRNA levels for 20S and 26S proteasome subunits, decreased protein levels of 20S proteasome subunits and the S14 non-ATPase subunit of the 26S proteasome, and impaired chymotrypsin- and trypsin-like activities of the enzyme. A combination of cisplatin and ifosfamide, two drugs that are widely used in the treatment of cancer patients, also depressed the expression of proteasomal subunits in muscles from rats bearing the MatB adenocarcinoma below basal levels. Thus, a down-regulation of ubiquitin-proteasome-dependent proteolysis is observed with various cytostatic agents and contributes to reverse the chemotherapy-induced muscle wasting.

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