Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
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Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. / Sakamoto, Kei; McCarthy, Afshan; Smith, Darrin; Green, Kevin A.; Hardie, D. Grahame; Ashworth, Alan; Alessi, Dario R.
In: EMBO Journal, Vol. 24, No. 10, 18.05.2005, p. 1810-1820.Research output: Contribution to journal › Journal article › Research › peer-review
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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.
PY - 2005/5/18
Y1 - 2005/5/18
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 AMPKα2. In LKB1-lacking muscle, the basal activity of the AMPKα2 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 AMPKα2. In LKB1-lacking muscle, the basal activity of the AMPKα2 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
UR - http://www.scopus.com/inward/record.url?scp=20044370885&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600667
DO - 10.1038/sj.emboj.7600667
M3 - Journal article
C2 - 15889149
AN - SCOPUS:20044370885
VL - 24
SP - 1810
EP - 1820
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 10
ER -
ID: 239777070