title: Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction.
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 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.
authors.affiliation: MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. k.sakamoto@dundee.ac.uk
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Darrin
authors.initials: D
authors.lastname: Smith
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Green
authors.forename: D
authors.initials: D
authors.lastname: Grahame Hardie
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010629:Phenformin / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D010629:Phenformin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; C031143:AICA ribonucleotide; D005947:Glucose