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Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction.

The EMBO journal | May 18, 2005

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 approximately 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 AMPKalpha2. In LKB1-lacking muscle, the basal activity of the AMPKalpha2 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.

Pubmed ID: 15889149 RIS Download

Mesh terms: AMP-Activated Protein Kinases | Aminoimidazole Carboxamide | Animals | Glucose | Integrases | Mice | Mice, Knockout | Multienzyme Complexes | Muscle Contraction | Muscle, Skeletal | Phenformin | Phenotype | Protein-Serine-Threonine Kinases | Ribonucleotides

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Mouse Genome Informatics (Data, Gene Annotation)

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