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Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR
Abstract
Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPKalpha2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases.
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“When the AMP:ATP ratio increases the probability of AMPK being in the AMP bound state increases.This allosterically activates AMPK [13] and makes AMPK a more efficient substrate for its upstream kinase LKB1, phosphorylation by which leads to full activation of the kinase [14].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [14]
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Self-citation
Metadata
- Authors
- Sakamoto, K., Göransson, O., Hardie, D. G., & Alessi, D. R.
- Affiliations
- University of Dundee (GB)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2004-08
- Volume
- 287
- Issue
- 2
- Pages
- E310-E317
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2050427373
- Cited by
- 299
- References
- 32
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 13 · 2015: 13 · 2014: 24 · 2013: 14 · 2012: 20
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- LKB1, AMPK, AMPK-related kinases, skeletal muscle, muscle contraction, phenformin, AICAR, AMPKα1, AMPKα2, MARK kinases, physical activity, type 2 diabetes, muscle fiber type, sciatic nerve stimulation
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Aminoimidazole Carboxamide, Animals, Cells, Cultured, Enzyme Activation, Fibroblasts, HeLa Cells, Humans, Hypoglycemic Agents, Isoenzymes, Male, Multienzyme Complexes, Muscle Contraction, Organ Culture Techniques, Phenformin, Physical Conditioning, Animal, Ribonucleotides, Rats, Wistar, Protein Serine-Threonine Kinases, Mice, Knockout, Muscle, Skeletal, Mice, Rats, AMP-Activated Protein Kinases
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