J. Anim Sci.
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Published online first on December 18, 2006
J. Anim Sci. 1990. doi:10.2527/jas.2006-342
© 2006 American Society of Animal Science
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J. Anim Sci., doi: 10.2527/jas.2006-342
©Copyright, 2006, The American Society of Animal Science

ARTICLE

Leucine stimulates mTOR signalling in C2C12 myoblasts in part through inhibition of AMP-activated protein kinase

M. Du 1*, Q. W. Shen 1, M. J. Zhu 1, S. P. Ford 1

1 Department of Animal Science, University of Wyoming, Laramie, WY 82071

* To whom correspondence should be addressed. E-mail: mindu{at}uwyo.edu.


  Abstract

Mammalian target of rapamycin (mTOR) signalling is one of the main signalling pathways controlling protein synthesis. Leucine treatment up-regulates mTOR signalling which enhances protein synthesis. However, mechanisms are not well understood. Here, leucine (2 mM) was used to treat C2C12 myoblast cells. Leucine treatment enhanced the phosphorylation of mTOR and ribosomal protein S6 kinase. Leucine treatment decreased the AMP/ATP ratio by 36.4 ± 9.1 % (P < 0.05) in myoblasts which was associated with a reduction in the phosphorylation of AMP-activated protein kinase (AMPK) {alpha} subunit at Thr172 (28.6 ± 4.9 % reduction, P < 0.05) and inhibition of AMPK activity (43.6 ± 3.5% reduction, P < 0.05). On the other hand, the phosphorylation of mTOR at Ser2448 was increased by 63.5 ± 10.0% (P < 0.05) and protein synthesis by 30.6 ± 6.1% (P < 0.05). Applying 5-aminoimidazole-4-carboxamide 1-beta-d-ribonucleoside (AICAr), an activator of AMPK, abolished the stimulation of leucine on mTOR signalling, showing that AMPK negatively controls mTOR signalling. To further show the role of AMPK in mTOR signalling, myoblasts expressing dominant negative AMPK{alpha} subunit (Negative) were employed. Negative myoblasts have very low AMPK activity. The activation of mTOR induced by leucine in these cells was abated, showing that AMPK contributed to mTOR activation. In conclusion, leucine stimulates mTOR signalling in part through AMPK inhibition. This study implicates that AMPK may be an important target for nutritional management to enhance mTOR signalling and protein synthesis in muscle cells, increasing muscle growth.

Key Words: skeletal muscle, leucine, mTOR, AMPK




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A. M. Pruznak, A. A. Kazi, R. A. Frost, T. C. Vary, and C. H. Lang
Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribonucleoside Prevents Leucine-Stimulated Protein Synthesis in Rat Skeletal Muscle
J. Nutr., October 1, 2008; 138(10): 1887 - 1894.
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