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| Subject Categories: Signal Transduction | Cellular Metabolism |
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| The EMBO Journal
(2005) 24, 1810–1820, doi:10.1038/sj.emboj.7600667 Published online 5 May 2005 |
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| Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction |
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| Kei Sakamoto1, Afshan McCarthy2, Darrin Smith2, Kevin A Green3, D Grahame Hardie3, Alan Ashworth2 and Dario R Alessi1 |
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1 MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK 2 The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK 3 Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, UK To whom correspondence should be addressed Kei Sakamoto, MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Tel.: +44 1382 34 4241; Fax: +44 1382 223 778; E-mail: k.sakamoto@dundee.ac.uk Received 22 December 2004; Accepted 31 March 2005; Published online 5 May 2005. |
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| Abstract |
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Recent studies indicate that the LKB1 tumour suppressor protein kinase is the major 'upstream' activator of the energy sensor AMP-activated protein kinase (AMPK). We have used mice in which LKB1 is expressed at only  10% of the normal levels in muscle and most other tissues, or that lack LKB1 entirely in skeletal muscle. Muscle expressing only 10% of the normal level of LKB1 had significantly reduced phosphorylation and activation of AMPK 2. In LKB1-lacking muscle, the basal activity of the AMPK2 isoform was greatly reduced and was not increased by the AMP-mimetic agent, 5-aminoimidazole-4-carboxamide riboside (AICAR), by the antidiabetic drug phenformin, or by muscle contraction. Moreover, phosphorylation of acetyl CoA carboxylase-2, a downstream target of AMPK, was profoundly reduced. Glucose uptake stimulated by AICAR or muscle contraction, but not by insulin, was inhibited in the absence of LKB1. Contraction increased the AMP:ATP ratio to a greater extent in LKB1-deficient muscles than in LKB1-expressing muscles. These studies establish the importance of LKB1 in regulating AMPK activity and cellular energy levels in response to contraction and phenformin. |
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| Keywords: AMP-activated protein kinase, glucose transport, LKB1, phenformin, skeletal muscle |
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