Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation.

Abstract

A number of acute wasting conditions are associated with an upregulation of the ubiquitin-proteasome system in skeletal muscle. Eicosapentaenoic acid (EPA) is effective in attenuating the increased protein catabolism in muscle in cancer cachexia, possibly due to inhibition of 15-hydroxyeicosatetraenoic acid (15-HETE) formation. To determine if a similar pathway is involved in other catabolic conditions, the effect of EPA on muscle protein degradation and activation of the ubiquitin-proteasome pathway has been determined during acute fasting in mice. When compared with a vehicle control group (olive oil) there was a significant decrease in proteolysis of the soleus muscles of mice treated with EPA after starvation for 24 h, together with an attenuation of the proteasome "chymotryptic-like" enzyme activity and the induction of the expression of the 20S proteasome alpha-subunits, the 19S regulator and p42, an ATPase subunit of the 19S regulator in gastrocnemius muscle, and the ubiquitin-conjugating enzyme E2(14k). The effect was not shown with the related (n-3) fatty acid docosahexaenoic acid (DHA) or with linoleic acid. However, 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-, 12- and 15-lipoxygenases also attenuated muscle protein catabolism, proteasome "chymotryptic-like" enzyme activity and expression of proteasome 20S alpha-subunits in soleus muscles from acute fasted mice. These results suggest that protein catabolism in starvation and cancer cachexia is mediated through a common pathway, which is inhibited by EPA and is likely to involve a lipoxygenase metabolite as a signal transducer.

• Authors: A S Whitehouse, M J Tisdale
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 285 Issue 3 Pg. 598-602 (Jul 20 2001) ISSN: 0006-291X [Print] United States
• PMID: 11453634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Benzoquinones
• Lipoxygenase Inhibitors
• Multienzyme Complexes
• Ubiquitins
• CV 6504
• Docosahexaenoic Acids
• Linoleic Acid
• Eicosapentaenoic Acid
• Endopeptidases
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• 26S proteasome non-ATPase regulatory subunit 13
• Adenosine Triphosphatases

Topics

• Acute Disease
• Adenosine Triphosphatases (metabolism)
• Administration, Oral
• Animals
• Benzoquinones (pharmacology)
• Cysteine Endopeptidases (metabolism)
• Docosahexaenoic Acids (administration & dosage)
• Eicosapentaenoic Acid (administration & dosage)
• Endopeptidases
• Enzyme Activation (drug effects)
• Female
• In Vitro Techniques
• Linoleic Acid (administration & dosage)
• Lipoxygenase Inhibitors (pharmacology)
• Mice
• Mice, Inbred Strains
• Multienzyme Complexes (antagonists & inhibitors, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Proteasome Endopeptidase Complex
• Signal Transduction
• Starvation (drug therapy, metabolism)
• Ubiquitins (metabolism)