Journal
EMBO JOURNAL
Volume 24, Issue 10, Pages 1810-1820Publisher
WILEY
DOI: 10.1038/sj.emboj.7600667
Keywords
AMP-activated protein kinase; glucose transport; LKB1; phenformin; skeletal muscle
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Funding
- MRC [MC_U127070193] Funding Source: UKRI
- Medical Research Council [MC_U127070193] Funding Source: Medline
- Breast Cancer Now [BREAST CANCER NOW RESEARCH CENTRE] Funding Source: Medline
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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 similar to 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 alpha 2. In LKB1-lacking muscle, the basal activity of the AMPKa2 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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