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

Kei Sakamoto, Afshan McCarthy, Darrin Smith, Kevin A. Green, D. Grahame Hardie, Alan Ashworth, Dario R. Alessi

    Research output: Contribution to journalArticlepeer-review

    417 Citations (Scopus)

    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 AMPK2. 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.
    Original languageEnglish
    Pages (from-to)1810-1820
    Number of pages11
    JournalThe EMBO Journal
    Volume24
    Issue number10
    DOIs
    Publication statusPublished - May 2005

    Keywords

    • AMP-activated protein kinase
    • Glucose transport
    • LKB1
    • Phenformin
    • Skeletal muscle

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