Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate

Smith, Helen J., Wyke, Stacey M. and Tisdale, Michael J. (2004). Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate. Cancer Research, 64 (23), pp. 8731-8735.

Abstract

The leucine metabolite β-hydroxy-β-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 μmol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome α- and β-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 μmol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor κBα and nuclear accumulation of nuclear factor κB. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.

Publication DOI: https://doi.org/10.1158/0008-5472.CAN-04-1760
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Uncontrolled Keywords: leucine metabolite beta-hydroxy-beta-methylbutyrate,HMB,muscle protein degradation,cancer-induced weight loss,ubiquitin-proteasome proteolytic pathway,tumor factor,proteolysis-inducing factor,PIF,murine myotubes,eicosapentaenoic acid,EPA,gene expression,Cancer Research,Oncology
Full Text Link: http://cancerre ... 64/23/8731.long
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2004-12
Authors: Smith, Helen J.
Wyke, Stacey M.
Tisdale, Michael J.

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