Molecular Mechanism by Which AMP-Activated Protein Kinase Activation Promotes Glycogen Accumulation in Muscle
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OBJECTIVE: During energy stress, AMP-activated protein kinase (AMPK) promotes glucose transport and glycolysis for ATP production, while it is thought to inhibit anabolic glycogen synthesis by suppressing the activity of glycogen synthase (GS) to maintain the energy balance in muscle. Paradoxically, chronic activation of AMPK causes an increase in glycogen accumulation in skeletal and cardiac muscles, which in some cases is associated with cardiac dysfunction. The aim of this study was to elucidate the molecular mechanism by which AMPK activation promotes muscle glycogen accumulation. RESEARCH DESIGN AND METHODS: We recently generated knock-in mice in which wild-type muscle GS was replaced by a mutant (Arg582Ala) that could not be activated by glucose-6-phosphate (G6P), but possessed full catalytic activity and could still be activated normally by dephosphorylation. Muscles from GS knock-in or transgenic mice overexpressing a kinase dead (KD) AMPK were incubated with glucose tracers and the AMPK-activating compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) ex vivo. GS activity and glucose uptake and utilization (glycolysis and glycogen synthesis) were assessed. RESULTS: Even though AICAR caused a modest inactivation of GS, it stimulated muscle glycogen synthesis that was accompanied by increases in glucose transport and intracellular [G6P]. These effects of AICAR required the catalytic activity of AMPK. Strikingly, AICAR-induced glycogen synthesis was completely abolished in G6P-insensitive GS knock-in mice, although AICAR-stimulated AMPK activation, glucose transport, and total glucose utilization were normal. CONCLUSIONS: We provide genetic evidence that AMPK activation promotes muscle glycogen accumulation by allosteric activation of GS through an increase in glucose uptake and subsequent rise in cellular [G6P].
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Acute treatment with AICAR promotes glycogen synthesis in skeletal muscle through a G6P-GS dependent pathway; an effect that is blunted in GS R582A KI mice.
“Recently, acute treatment with AICAR was shown to promote glycogen synthesis in skeletal muscle through a G6P-GS dependent pathway; an effect that is blunted in GS R582A KI mice [137].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [137]
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- Authors
- Hunter, R. W., Treebak, J. T., Wojtaszewski, J. F. P., & Sakamoto, K.
- Affiliations
- University of Dundee (GB)
- University of Copenhagen (DK)
- Corresponding author
- Hunter, Roger W.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-02-21
- Volume
- 60
- Issue
- 3
- Pages
- 766-774
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3046837
- OpenAlex
- W2105508989
- Cited by
- 151
- References
- 50
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 11 · 2018: 8 · 2017: 9 · 2016: 22 · 2015: 14 · 2014: 12 · 2013: 8 · 2012: 16
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- AstraZeneca
- University of Pennsylvania
- University of Dundee
- British Heart Foundation (PG/09/059, PG/09/059/27851)
- Diabetes UK (07/0003529)
- 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
- AMPK, glycogen synthesis, glycogen synthase, allosteric activation, glucose-6-phosphate, glucose transport, skeletal muscle, myocardium, AICAR, energy stress, glucose utilization
- MeSH terms
- Aminoimidazole Carboxamide, Analysis of Variance, Animals, Glycogen, Glycogen Synthase, Mice, Transgenic, Phosphorylation, Ribonucleotides, Blotting, Western, Signal Transduction, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Mice, AMP-Activated Protein Kinases
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