Attenuation of proteasome-induced proteolysis in skeletal muscle by {beta}-hydroxy-{beta}-methylbutyrate in cancer-induced muscle loss.
Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite beta-hydroxy-beta-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 alpha or beta 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.
Smith
Helen J
HJ
Pharmaceutical Sciences Research Institute, Aston University, Birmingham, United Kingdom.
Mukerji
Pradip
P
Tisdale
Michael J
MJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental; D046988:Proteasome Endopeptidase Complex; D014631:Valerates / Q000494:pharmacology* / Q000627:therapeutic use; D019282:Wasting Syndrome / Q000188:drug therapy*; D015431:Weight Loss / Q000187:drug effects*
D009363:Neoplasm Proteins; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; D015118:Eicosapentaenoic Acid; D046988:Proteasome Endopeptidase Complex