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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/E1409    most recent 90530.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Eley, H. L. Articles by Tisdale, M. J. Search for Related Content PubMed PubMed Citation Articles by Eley, H. L. Articles by Tisdale, M. J.

Attenuation of depression of muscle protein synthesis induced by lipopolysaccharide, tumor necrosis factor, and angiotensin II by β-hydroxy-β-methylbutyrate

Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom

Submitted 7 July 2008 ; accepted in final form 8 October 2008

β-Hydroxy-β-methylbutyrate (HMB; 50 µM) has been shown to attenuate the depression in protein synthesis in murine myotubes in response to lipopolysaccharide (LPS), tumor necrosis factor- (TNF-) with or without interferon- (IFN-), and angiotensin II (ANG II). The mechanism for the depression of protein synthesis by all three agents was the same and was attributed to activation of double-stranded RNA-dependent protein kinase (PKR) with the subsequent phosphorylation of eukaryotic initiation factor 2 (eIF2) on the -subunit as well as increased phosphorylation of the elongation factor (eEF2). Myotubes expressing a catalytically inactive PKR variant, PKR6, showed no depression of protein synthesis in response to either LPS or TNF-, confirming the importance of PKR in this process. There was no effect of any of the agents on phosphorylation of mammalian target of rapamycin (mTOR) or initiation factor 4E-binding protein (4E-BP1), and thus no change in the amount of eIF4E bound to 4E-BP1 or the concentration of the active eIF4E·eIF4G complex. HMB attenuated phosphorylation of eEF2, possibly by increasing phosphorylation of mTOR, and also attenuated phosphorylation of eIF2 by preventing activation of PKR. These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions.

eukaryotic initiation factor 2