Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation.
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.
Whitehouse
A S
AS
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, United Kingdom.
Tisdale
M J
MJ
D000208:Acute Disease; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage*; D010450:Endopeptidases; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D019787:Linoleic Acid / Q000008:administration & dosage; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D015398:Signal Transduction; D013217:Starvation / Q000188:drug therapy* / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D009097:Multienzyme Complexes; D014452:Ubiquitins; C067513:CV 6504; D004281:Docosahexaenoic Acids; D019787:Linoleic Acid; D015118:Eicosapentaenoic Acid; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases