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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/E923    most recent 00314.2007v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) 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.

Signaling pathways initiated by -hydroxy--methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli

¹Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom; and ²Ross Products Division, Abbott Laboratories, Columbus, Ohio

Submitted 29 May 2007 ; accepted in final form 2 July 2007

To investigate the mechanism by which -hydroxy--methylbutyrate (HMB) attenuates the depression of protein synthesis in the skeletal muscle of cachectic mice, a study has been carried out in murine myotubes in the presence of proteolysis-inducing factor (PIF). PIF inhibited protein synthesis by 50% within 4 h, and this was effectively attenuated by HMB (25–50 µM). HMB (50 µM) alone stimulated protein synthesis, and this was attenuated by rapamycin (27 nM), an inhibitor of mammalian target of rapamycin (mTOR). Further evidence for an involvement of this pathway was shown by an increased phosphorylation of mTOR, the 70-kDa ribosomal S6 kinase (p70^S6k), and initiation factor 4E-binding protein (4E-BP1) and an increased association of eukaryotic initiation factor 2 (eIF4E) with eIF4G. PIF alone induced a transient (1–2 h) stimulation of phosphorylation of mTOR and p70^S6k. However, in the presence of HMB, phosphorylation of mTOR, p70^S6k, and 4E-BP1 was increased, and inactive 4E-BP1-eIF4E complex was reduced, whereas the active eIF4G·eIF4E complex was increased, suggesting continual stimulation of protein synthesis. HMB alone reduced phosphorylation of elongation factor 2, but this effect was not seen in the presence of PIF. PIF induced autophosphorylation of the double-strand RNA-dependent protein kinase (PKR), leading to phosphorylation of eIF2 on the -subunit, which would inhibit protein synthesis. However, in the presence of HMB, phosphorylation of PKR and eIF2 was attenuated, and this was also observed in skeletal muscle of cachectic mice administered HMB (0.25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms.

proteolysis-inducing factor; eukaryotic initiation factor 2; 4E-binding protein 1

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