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

TY - JOUR

T1 - Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction

AU - Sakamoto, Kei

AU - McCarthy, Afshan

AU - Smith, Darrin

AU - Green, Kevin A.

AU - Hardie, D. Grahame

AU - Ashworth, Alan

AU - Alessi, Dario R.

N1 - dc.publisher: Nature Publishing Group

PY - 2005/5

Y1 - 2005/5

N2 - 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.

AB - 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.

KW - AMP-activated protein kinase

KW - Glucose transport

KW - LKB1

KW - Phenformin

KW - Skeletal muscle

U2 - 10.1038/sj.emboj.7600667

DO - 10.1038/sj.emboj.7600667

M3 - Article

SN - 1460-2075

VL - 24

SP - 1810

EP - 1820

JO - The EMBO Journal

JF - The EMBO Journal

IS - 10

ER -