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

Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1409-16. doi: 10.1152/ajpendo.90530.2008. Epub 2008 Oct 14.


beta-Hydroxy-beta-methylbutyrate (HMB; 50 microM) has been shown to attenuate the depression in protein synthesis in murine myotubes in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) with or without interferon-gamma (IFN-gamma), 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 alpha-subunit as well as increased phosphorylation of the elongation factor (eEF2). Myotubes expressing a catalytically inactive PKR variant, PKRDelta6, showed no depression of protein synthesis in response to either LPS or TNF-alpha, 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 eIF2alpha by preventing activation of PKR. These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Angiotensin II / adverse effects
  • Angiotensin II / pharmacology*
  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factor-4G / metabolism
  • Eukaryotic Initiation Factors
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / biosynthesis*
  • Muscular Atrophy / chemically induced
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / prevention & control
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Biosynthesis / drug effects*
  • Tumor Necrosis Factors / pharmacology*
  • Valerates / pharmacology*
  • Valerates / therapeutic use
  • eIF-2 Kinase / metabolism


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Eukaryotic Initiation Factors
  • Lipopolysaccharides
  • Muscle Proteins
  • Phosphoproteins
  • Tumor Necrosis Factors
  • Valerates
  • Angiotensin II
  • beta-hydroxyisovaleric acid
  • eIF-2 Kinase