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Centre de Recherches en Nutrition Humaine, Unité d'Etude du Métabolisme Azoté [S. T., D. T., E. A., D. L., D. A.], and Unité de Recherches sur l'Expression des Protéases [A. O., D. B., M. F.], INRA de Theix, 63122 Ceyrat, France, and Departmento de Fisiologia, Universitat de Valencia, Av. Blasco Ibanez 17, 46010 Valencia, Spain [M. A., J. M. E.]
Little information is available on proteolytic pathways responsible for muscle wasting in cancer cachexia. Experiments were carried out in young rats to demonstrate whether a small (<0.3% body weight) tumor may activate the lysosomal, Ca2+-dependent, and/or ATP-ubiquitin-dependent proteolytic pathway(s) in skeletal muscle. Five days after tumor implantation, protein mass of extensor digitorum longus and tibialis anterior muscles close to a Yoshida sarcoma was significantly reduced compared to the contralateral muscles. According to in vitro measurements, protein loss totally resulted from increased proteolysis and not from depressed protein synthesis. Inhibitors of lysosomal and Ca2+-dependent proteases did not attenuate increased rates of proteolysis in the atrophying extensor digitorum longus. Accordingly, cathepsin B and B+L activities, and mRNA levels for cathepsin B were unchanged. By contrast, ATP depletion almost totally suppressed the increased protein breakdown. Furthermore, mRNA levels for ubiquitin, 14 kDa ubiquitin carrier protein E2, and the C8 or C9 proteasome subunits increased in the atrophying muscies. Similar adaptations occurred in the muscles from cachectic animals 12 days after tumor implantation. These data strongly suggest that the activation of the ATP-ubiquitin-dependent proteolytic pathway is mainly responsible for muscle atrophy in Yoshida sarcoma-bearing rats.
1 This study was supported by research grants from the Association pour la Recherche sur le Cancer, the Conseil Régional d'Auvergne, the French Ministères des Affaires Etrangères (Actions Intégrées Franco-Espagnoles 1991–1992) et de l'Enseignement Supérieur et de la Recherche, and the Institut National de la Recherche Agronomique.
2 To whom requests for reprints should be addressed, at INRA de Theix, Unité d'Etude du Métabolisme Azoté, 63122 CEYRAT, France.
Received 6/ 8/94. Accepted 9/ 2/94.
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