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Cited by 261Metabolism, Diabetes, and CancerGlycogen Storage Diseases and MyoclonusBiochemical and Molecular Research

Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle

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Wojtaszewski, Jørgen F.P., Jørgensen, Sebastian B., Hellsten, Ylva, Hardie, D. Grahame, Richter, Erik A.·2002·Diabetes
DOI 10.2337/diabetes.51.2.284
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Abstract

5′-AMP-activated protein kinase (AMPK) functions as a metabolic switch in mammalian cells and can be artificially activated by 5-aminoimidazole-4-carboxamide (AICA)-riboside. AMPK activation during muscle contraction is dependent on muscle glycogen concentrations, but whether glycogen also modifies the activation of AMPK and its possible downstream effectors (glycogen synthase and glucose transport) by AICA-riboside in resting muscle is not known. Thus, we have altered muscle glycogen levels in rats by a combination of swimming exercise and diet and investigated the effects of AICA-riboside in the perfused rat hindlimb muscle. Two groups of rats, one with super-compensated muscle glycogen content (∼200–300% of normal; high glycogen [HG]) and one with moderately lowered muscle glycogen content (∼80% of normal; low glycogen [LG]), were generated. In both groups, the degree of activation of the α2 isoform of AMPK by AICA-riboside depended on muscle type (white gastrocnemius ≫ red gastrocnemius > soleus). Basal and AICA-riboside-induced α2-AMPK activity were markedly lowered in the HG group (∼50%) compared with the LG group. Muscle 2-deoxyglucose uptake was also increased and glycogen synthase activity decreased by AICA-riboside. Especially in white gastrocnemius, these effects, as well as the absolute activity levels of AMPK-α2, were markedly reduced in the HG group compared with the LG group. The inactivation of glycogen synthase by AICA-riboside was accompanied by decreased gel mobility and was eliminated by protein phosphatase treatment. We conclude that acute AICA-riboside treatment leads to phosphorylation and deactivation of glycogen synthase in skeletal muscle. Although the data do not exclude a role of other kinases/phosphatases, they suggest that glycogen synthase may be a target for AMPK in vivo. Both basal and AICA-riboside-induced AMPK-α2 and glycogen synthase activities, as well as glucose transport, are depressed when the glycogen stores are plentiful. Because the glycogen level did not affect adenine nucleotide concentrations, our data suggest that glycogen may directly affect the activation state of AMPK in skeletal muscle.

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  • Phosphorylation of GS at site 2 (S7) by AMPK inhibits enzyme activity in isolated muscles treated with AICAR.

    “This inhibits enzyme activity in isolated muscles treated with AICAR [133-135].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [134]

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Authors
Wojtaszewski, J. F. P., Jørgensen, S. B., Hellsten, Y., Hardie, D. G., & Richter, E. A.
Affiliations
  • University of Copenhagen (DK)
  • University of Dundee (GB)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2002-02-01
Volume
51
Issue
2
Pages
284-292
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.51.2.284
OpenAlex
W2156518233
Cited by
261
References
52
Citations by year
2026: 1 · 2025: 3 · 2023: 3 · 2022: 10 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 10 · 2017: 4 · 2016: 10 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 14
FWCI
8.34
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Wellcome Trust
  • National Research Foundation
  • Danmarks Grundforskningsfond (504–14)
  • Novo Nordisk
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
AICA riboside, AMPK, glycogen synthase, skeletal muscle glycogen, glucose transport, 2-deoxyglucose uptake, muscle fiber type, protein phosphatase, muscle glycogen content, swimming training, metabolic switch
MeSH terms
Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Animal Feed, Deoxyglucose, Glycogen, Glycogen Synthase, Isoenzymes, Male, Motor Activity, Multienzyme Complexes, Protein Kinases, Ribonucleosides, Ribonucleotides, Swimming, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Rats, AMP-Activated Protein Kinases

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