Article

Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside prevents leucine-stimulated protein synthesis in rat skeletal muscle.

Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, PA 17033, USA.
Journal of Nutrition (impact factor: 3.92). 11/2008; 138(10):1887-94. pp.1887-94
Source: PubMed

ABSTRACT Several stress conditions are characterized by activation of 5'-AMP-activated protein kinase (AMPK) and the development of leucine resistance in skeletal muscle. In the present study, we determined whether direct activation of the AMPK by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) prevents the characteristic leucine-induced increase in protein synthesis by altering mammalian target of rapamycin (mTOR) signal transduction. Rats were injected with AICAR or saline (Sal) and 1 h thereafter received an oral gavage of leucine (or Sal). Efficacy of AICAR was verified by increased AMPK phosphorylation. AICAR decreased basal in vivo muscle (gastrocnemius) protein synthesis and completely prevented the leucine-induced increase, independent of a change in muscle adenine nucleotide concentration. AICAR also prevented the hyperphosphorylation of eukaryotic initiation factor (eIF) 4E binding protein (4E-BP1), ribosomal protein S6 kinase (S6K1), S6, and eIF4G in response to leucine, suggesting a decrease in mTOR activity. Moreover, AICAR prevented the leucine-induced redistribution of eIF4E from the inactive eIF4E.4E-BP1 to the active eIF4E.eIF4G complex. This ability of AICAR to produce muscle leucine resistance could not be attributed to a change in phosphorylation of tuberous sclerosis complex (TSC)2, the formation of a TSC1.TSC2 complex, the binding of raptor with mTOR, or the phosphorylation of eukaryotic elongation factor-2. However, the inhibitory actions of AICAR were associated with reduced phosphorylation of proline-rich Akt substrate-40 and increased phosphorylation of raptor, which represent potential mechanisms by which AICAR might be expected to inhibit leucine-induced increases in mTOR activity and protein synthesis under in vivo conditions.

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Keywords

5'-AMP-activated protein kinase
 
active eIF4E.eIF4G complex
 
altering mammalian target
 
characteristic leucine-induced increase
 
direct activation
 
eukaryotic elongation factor-2
 
eukaryotic initiation factor
 
inhibitory actions
 
leucine resistance
 
leucine-induced increase
 
leucine-induced increases
 
leucine-induced redistribution
 
muscle adenine nucleotide concentration
 
muscle leucine resistance
 
proline-rich Akt substrate-40
 
ribosomal protein S6 kinase
 
skeletal muscle
 
TSC1.TSC2 complex
 
tuberous sclerosis complex
 
vivo muscle