AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise
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AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.
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Functional AMPK is critical in maintaining muscle mitochondrial content.
“researchers have used the muscle-specific double knockout AMPK β1 and β2 mouse model (β1β2M-KO) to demonstrate functional AMPK is critical in maintaining muscle mitochondrial content (O'neill et al., 2011).”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as O'neill et al., 2011
Exercise can regulate glucose uptake by an insulin-independent mechanism involving AMPK.
“Exercise can also regulate glucose uptake by an insulin-independent mechanism involving AMPK [30].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
AMPK β1β2M-KO mice have undetectable levels of AMPK activity at rest or during exercise.
“As anticipated, AMPK β1β2M-KO mice have undetectable levels of AMPK activity at rest or during exercise [30].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
Young AMPK β1β2M-KO mice have similar whole-body weight and adiposity compared to wild-type littermates.
“Interestingly, young (9 to 12 weeks) AMPK β1β2M-KO mice have similar whole-body weight and adiposity, and consistent with this, whole-body and skeletal muscle specific insulin sensitivity is similar when compared to wild-type littermates [30].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
Whole-body and skeletal muscle specific insulin sensitivity is similar in young AMPK β1β2M-KO mice compared to wild-type littermates.
“Interestingly, young (9 to 12 weeks) AMPK β1β2M-KO mice have similar whole-body weight and adiposity, and consistent with this, whole-body and skeletal muscle specific insulin sensitivity is similar when compared to wild-type littermates [30].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
AMPK β1β2M-KO mice have dramatically reduced voluntary wheel activity (75%), maximal exercise capacity (95%), mitochondrial content (30%) and exercise-mediated glucose uptake in skeletal muscle (55% to 70%).
“Their phenotype is more dramatic compared to whole-body AMPK β2 KO mice [28] and is characterized by dramatically reduced voluntary wheel activity (75%), maximal exercise capacity (95%), mitochondrial content (30%) and exercise-mediated glucose uptake in skeletal muscle (55% to 70%) [30].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle.
“In support of this, insulin also does not increase AMPK T172 or ACC S79/212 phosphorylation [74] and AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle [26,28,30,36,100] despite blunted TBC1D1 PAS and T590 phosphorylation in response to insulin [30,74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
TBC1D1 expression is reduced by ~50% in skeletal muscle of AMPK α2 KO, α2 KD, α2iTg and β1β2 M-KO mice.
“In contrast, TBC1D1 expression is reduced by ~50% in skeletal muscle of AMPK α2 KO, α2 KD, α2iTg and β1β2 M-KO mice [30,74,102,117], and this may be compensatory for the lack of phosphorylation and inhibition by AMPK, or alternatively, reduced muscle glucose uptake in AMPK β1β2 M-KO mice.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
Only when AMPK activity is completely abolished, as in β1β2 M-KO mice, are more dramatic reductions in glucose uptake observed, similar to LKB1-MKO mice.
“It appears that only when AMPK activity is completely abolished, as in β1β2 M-KO mice, that more dramatic reductions in glucose uptake are observed [30], which are similar to that observed in LKB1-MKO mice [18].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions.
“TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions [30,74], suggesting that AMPK is important for PAS phosphorylation in response to contraction.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [30]
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- Authors
- O'Neill, H. M., Maarbjerg, S. J., Crane, J. D., Jeppesen, J., Jørgensen, S. B., Schertzer, J. D., Shyroka, O., Kiens, B., van Denderen, B. J., Tarnopolsky, M. A., Kemp, B. E., Richter, E. A., & Steinberg, G. R.
- Affiliations
- Department of Medicine, McMaster University, Hamilton, ON, Canada L8N 3Z5;
- University of Copenhagen (DK)
- McMaster University (CA)
- Novo Nordisk (Denmark) (DK)
- St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia;
- The University of Melbourne (AU)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-09-06
- Volume
- 108
- Issue
- 38
- Pages
- 16092-16097
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3179037
- OpenAlex
- W2140808124
- Cited by
- 406
- References
- 51
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 17 · 2023: 14 · 2022: 22 · 2021: 27 · 2020: 28 · 2019: 29 · 2018: 26 · 2017: 38 · 2016: 38 · 2015: 41 · 2014: 38 · 2013: 34 · 2012: 24
- FWCI
- 12.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- McMaster University
- University of Melbourne
- State Government of Victoria
- H. Lundbeck A/S
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- AMPK, skeletal muscle, exercise capacity, muscle metabolism, AMPK knockout mice, treadmill running
- MeSH terms
- Animals, DNA, Mitochondrial, Female, Glucose, Hypoglycemic Agents, Insulin, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Muscle Contraction, Physical Conditioning, Animal, Immunoblotting, Mice, Knockout, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Mitochondrial Proteins, Microscopy, Electron, Transmission, Mice, AMP-Activated Protein Kinases
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