Mann muss den Wirkungsmechanismus verstehen ( kennen ) um zu wissen, wie HMB
Smith HJ, Wyke SM, Tisdale MJ.
Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by beta-hydroxy-beta-methylbutyrate.
Cancer Res. 2004 Dec 1;64(23):8731-5. https://www.ncbi.nlm.nih.gov/entrez/q..._uids=15574784
The leucine metabolite beta-hydroxy-beta-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 mumol/L, EPA
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 alpha- and beta-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
at a concentration of 50 mumol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor kappaBalpha and nuclear accumulation of nuclear factor kappaB. EPA
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.
Taillandier D, Combaret L, Pouch MN, Samuels SE, Bechet D, Attaix D.
The role of ubiquitin-proteasome-dependent proteolysis in the remodelling of skeletal muscle. Proc Nutr Soc. 2004 May;63(2):357-61. Review. https://www.ncbi.nlm.nih.gov/entrez/q..._uids=15294055
In skeletal muscle, as in any mammalian tissue, protein levels are dictated by relative rates of protein synthesis and breakdown. Recent studies have shown that the ubiquitin-proteasome-dependent proteolytic pathway is mainly responsible for the breakdown of myofibrillar proteins. In this pathway proteins that are to be degraded are first tagged with a polyubiquitin degradation signal. Ubiquitination is performed by the ubiquitin-activating enzyme, ubiquitin-conjugating enzymes
and ubiquitin-protein ligases, which are responsible for the recognition of specific substrates. Polyubiquitinated protein substrates are then specifically recognised and degraded by the 26S proteasome. The present review focuses on: (1) the mechanisms of ubiquitination-deubiquitination that make the system highly selective; (2) the mechanisms of proteolysis in skeletal muscle. In particular, the role of the system in the remodelling of skeletal muscle during exercise and disuse and in recovery or regeneration that prevails during post-atrophic conditions is reviewed.