Attenuation of proteasome-induced proteolysis in skeletal muscle by beta-hydroxy-beta-methylbutyrate in cancer-induced muscle loss

Helen J. Smith, Pradip Mukerji, Michael J. Tisdale

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)277-283
Number of pages7
JournalCancer Research
Volume65
Issue number1
Publication statusPublished - Jan 2005

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Muscle Neoplasms
Proteasome Endopeptidase Complex
Eicosapentaenoic Acid
Proteolysis
Skeletal Muscle
Weight Loss
Ubiquitin-Conjugating Enzymes
Neoplasms
Proteins
Ubiquitin
Leucine
Adenosine Triphosphatases
Down-Regulation
Body Weight
beta-hydroxyisovaleric acid
Weights and Measures
Survival
Therapeutics
Growth

Bibliographical note

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Keywords

  • cachexia
  • muscle proteolysis
  • proteasome proteolysis
  • β-hydroxy-β-methylbutyrate

Cite this

Smith, Helen J. ; Mukerji, Pradip ; Tisdale, Michael J. / Attenuation of proteasome-induced proteolysis in skeletal muscle by beta-hydroxy-beta-methylbutyrate in cancer-induced muscle loss. In: Cancer Research. 2005 ; Vol. 65, No. 1. pp. 277-283.
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Attenuation of proteasome-induced proteolysis in skeletal muscle by beta-hydroxy-beta-methylbutyrate in cancer-induced muscle loss. / Smith, Helen J.; Mukerji, Pradip; Tisdale, Michael J.

In: Cancer Research, Vol. 65, No. 1, 01.2005, p. 277-283.

Research output: Contribution to journalArticle

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AU - Smith, Helen J.

AU - Mukerji, Pradip

AU - Tisdale, Michael J.

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