Glucocorticoids oppose translational control by leucine in skeletal muscle

  • Shah O
  • Anthony J
  • Kimball S
 et al. 
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Abstract

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.

Author-supplied keywords

  • Animals
  • Dexamethasone/pharmacology
  • Electrophoresis, Polyacrylamide Gel
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Glucocorticoids/ pharmacology
  • Humans
  • Leucine/ pharmacology
  • Male
  • Mice
  • Muscle Proteins/biosynthesis/genetics
  • Muscle, Skeletal/ metabolism
  • Peptide Initiation Factors/metabolism
  • Phosphorylation
  • Protein Biosynthesis/ drug effects
  • RNA, Messenger/metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases/metabolism

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Authors

  • O J Shah

  • J C Anthony

  • S R Kimball

  • L S Jefferson

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