Article
- The EMBO Journal (2005) 24, 1810 - 1820
- doi:10.1038/sj.emboj.7600667
Published online: 5 May 2005
Subject Categories:
Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
Kei Sakamoto1, Afshan McCarthy2, Darrin Smith2, Kevin A Green3, D Grahame Hardie3, Alan Ashworth2 and Dario R Alessi1
- MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK
- The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
- Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, UK
Correspondence to:
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
Abstract
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.
Keywords:
- AMP-activated protein kinase,
- glucose transport,
- LKB1,
- phenformin,
- skeletal muscle
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