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Chemotherapy inhibits skeletal muscle ubiquitin-proteasome-dependent proteolysis
Thomas Tilignac1, Sandrine Temparis, Lydie Combaret
1Human Nutrition Research Center, Nutrition and Protein Metabolism Unit, Institut National de la Recherche Agronomique de Theix, 63122 Ceyrat, France.
Abstract:
Chemotherapy has cachectic effects, but it is unknown whether cytostatic agents alter skeletal muscle 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.
Insights
Cytostatic chemotherapy agents, like cystemustine, initially cause muscle wasting but then decrease proteolysis via the ubiquitin-proteasome system, reversing muscle loss. This mechanism was observed in mice and rats with various cancer models.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Chemotherapy can induce muscle wasting (cachexia), but its precise effects on skeletal muscle proteolysis remain unclear.
- The ubiquitin-proteasome pathway is a key regulator of protein degradation in muscle cells.
Purpose of the Study:
- To investigate whether cytostatic agents alter skeletal muscle proteolysis.
- To determine the impact of cystemustine on protein degradation in healthy and tumor-bearing mice.
- To explore the mechanisms underlying chemotherapy-induced changes in muscle proteolysis.
Main Methods:
- Administered cystemustine to healthy and colon 26 adenocarcinoma-bearing mice.
- Assessed muscle wasting and protein loss post-treatment.
- Quantified rates of muscle proteolysis and measured proteasome subunit expression and activity.
- Examined the effects of cisplatin and ifosfamide on proteasomal subunits in rats.
Main Results:
- Cystemustine induced muscle wasting but subsequently decreased proteolysis below basal levels, leading to cessation of muscle loss.
- Proteasome-dependent proteolysis was inhibited by reduced proteasome subunit mRNA and protein levels, and impaired enzyme activity.
- Cisplatin and ifosfamide also downregulated proteasomal subunit expression in tumor-bearing rats.
- These findings demonstrate a consistent down-regulation of ubiquitin-proteasome-dependent proteolysis by cytostatic agents.
Conclusions:
- Cytostatic agents can reverse chemotherapy-induced muscle wasting by down-regulating ubiquitin-proteasome-dependent proteolysis.
- The observed inhibition involves reduced proteasome expression and activity.
- This pathway modulation offers a potential therapeutic target for managing cancer cachexia.