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Attenuation of Proteasome-Induced Proteolysis in Skeletal Muscle by ß-Hydroxy-ß-Methylbutyrate in Cancer-Induced Muscle Loss

¹ Pharmaceutical Sciences Research Institute, Aston University, Birmingham, United Kingdom and ² Ross Products Division, Abbott Laboratories, Columbus, Ohio, USA

Requests for reprints: Michael J. Tisdale, Pharmaceutical Sciences Research Institute, Aston University, Birmingham, B4 7ET, United Kingdom. Phone: 44-121-359-3611; Fax: 44-121-333-3172; E-mail: m.j.tisdale{at}aston.ac.uk

Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite ß-hydroxy-ß-methylbutyrate (HMB) on the reduction of body weight loss and protein degradation in the MAC16 model of cancer-induced weight loss has been compared with that of eicosapentaenoic acid (EPA), a recognized inhibitor of protein degradation. HMB was found to attenuate the development of weight loss at a dose greater than 0.125 g/kg accompanied by a small reduction in tumor growth rate. When EPA was used at a suboptimal dose level (0.6 g/kg) the combination with HMB seemed to enhance the anticachectic effect. Both treatments caused an increase in the wet weight of soleus muscle and a reduction in protein degradation, although there did not seem to be a synergistic effect of the combination. Proteasome activity, determined by the "chymotrypsin-like" enzyme activity, was attenuated by both HMB and EPA. Protein expression of the 20S or ß subunits was reduced by at least 50%, as were the ATPase subunits MSS1 and p42 of the 19S proteasome regulatory subunit. This was accompanied by a reduction in the expression of E2_14k ubiquitin-conjugating enzyme. The combination of EPA and HMB was at least as effective or more effective than either treatment alone. Attenuation of proteasome expression was reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB. In addition, HMB produced a significant stimulation of protein synthesis in skeletal muscle. These results suggest that HMB preserves lean body mass and attenuates protein degradation through down-regulation of the increased expression of key regulatory components of the ubiquitin-proteasome proteolytic pathway, together with stimulation of protein synthesis.

Key Words: cachexia • muscle proteolysis • proteasome proteolysis • ß-hydroxy-ß-methylbutyrate

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