Mechanism of attenuation by β-hydroxy-β-methylbutyrate of muscle protein degradation induced by lipopolysaccharide

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Authors

  • Steven T. Russell
  • Michael J. Tisdale

Research units

Abstract

The mechanism of the effect of β-hydroxy-β-methylbutyrate (HMB) on protein degradation induced by lipopolysaccharide (LPS) has been evaluated in murine myotubes. HMB (50 μM) completely attenuated total protein degradation induced by LPS (1-100 ng/ml), formation of reactive oxygen species (ROS) and activation of caspase-3/-8. Specific inhibitors of caspase-3/-8 completely attenuated ROS production, total protein degradation and the LPS-induced autophosphorylation of dsRNA-dependent protein kinase (PKR). Protein degradation in response to LPS or ROS production was not seen in myotubes transfected with mutant PKRΔ6, suggesting that PKR was involved in ROS production, which was essential for total protein degradation. This was confirmed using the antioxidant butylated hydroxytoluene (BHT) which completely attenuated protein degradation in response to LPS. The link between PKR activation and ROS production was mediated through p38 mitogen-activated protein kinase (MAPK), which was activated by LPS in myotubes transfected with wild-type PKR, but not PKRΔ6. Both ROS production and protein degradation induced by LPS were completely attenuated by SB203580, a specific inhibitor of p38MAPK. This suggests that LPS induces protein degradation through a signalling cascade involving activation of caspase-3/-8, activation of PKR and production of ROS through p38MAPK, and that this process is attenuated by HMB.

Details

Original languageEnglish
Pages (from-to)171-179
Number of pages9
JournalMolecular and Cellular Biochemistry
Volume330
Issue number1-2
Early online date30 Apr 2009
DOIs
Publication statusPublished - Oct 2009

    Keywords

  • lipopolysaccharide, muscle proteolysis, protein kinase R, reactive oxygen species

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