Glucocorticoids oppose translational control by leucine in skeletal muscle

Glucocorticoids comprise an important class of hormonal mediators of fuel a nd protein homeostasis in normal and pathological scenarios. In skeletal mu scle, exposure to glucocorticoids is characterized by a reduction in protei n synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is s imply due to inhibition of the basally activated translational apparatus. T herefore, this inquiry was designed to determine whether leucine, administe red orally, could rescue the translational inhibition induced by glucocorti coids. Dexamethasone, injected intraperitoneally, acutely diminished protei n synthetic rates to 80% of control values in skeletal muscle from rat hind limb. The eukaryotic initiation factor (eIF)4 regulatory element was simult aneously and negatively impacted via sequestration of eIF4E by the hypophos phorylated form of the translational suppressor, eIF4E binding protein 1 (4 E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphoryl ated, notably at T389, in response to glucocorticoids. Leucine, administere d orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the trans lational machinery, and indeed of protein turnover in general, is widely ap preciated, this amino acid may prove useful in normalizing the impairment o f mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.