Activation of AMPKα2 Is Not Crucial for Mitochondrial Uncoupling-Induced Metabolic Effects but Required to Maintain Skeletal Muscle Integrity
Open accessAbstract
Transgenic (UCP1-TG) mice with ectopic expression of UCP1 in skeletal muscle (SM) show a phenotype of increased energy expenditure, improved glucose tolerance and increase substrate metabolism in SM. To investigate the potential role of skeletal muscle AMPKα2 activation in the metabolic phenotype of UCP1-TG mice we generated double transgenic (DTG) mice, by crossing of UCP1-TG mice with DN-AMPKα2 mice overexpressing a dominant negative α2 subunit of AMPK in SM which resulted in an impaired AMPKα2 activity by 90±9% in SM of DTG mice. Biometric analysis of young male mice showed decreased body weight, lean and fat mass for both UCP1-TG and DTG compared to WT and DN-AMPKα2 mice. Energy intake and weight-specific total energy expenditure were increased, both in UCP1-TG and DTG mice. Moreover, glucose tolerance, insulin sensitivity and fatty acid oxidation were not altered in DTG compared to UCP1-TG. Also uncoupling induced induction and secretion of fibroblast growth factor 21 (FGF21) from SM was preserved in DTG mice. However, voluntary physical cage activity as well as ad libitum running wheel access during night uncovered a severe activity intolerance of DTG mice. Histological analysis showed a progressive degenerative morphology in SM of DTG mice which was not observed in SM of UCP1-TG mice. Moreover, ATP-depletion related cellular stress response via heat shock protein 70 was highly induced, whereas capillarization regulator VEGF was suppressed in DTG muscle. In addition, AMPKα2-mediated induction of mitophagy regulator ULK1 was suppressed in DTG mice, as well as mitochondrial respiratory capacity and content. In conclusion, we demonstrate that AMPKα2 is dispensable for SM mitochondrial uncoupling induced metabolic effects on whole body energy balance, glucose homeostasis and insulin sensitivity. But strikingly, activation of AMPKα2 seems crucial for maintaining SM function, integrity and the ability to compensate chronic metabolic stress induced by SM mitochondrial uncoupling.
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Mice overexpressing UCP-1 and a dominant negative form of AMPKα2 also show similar intolerance to physical activity and degeneration of smooth muscle cells.
“Moreover, these mice also showed a similar intolerance to physical activity and a degeneration of smooth muscle cells [259].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [259]
AMPK phosphorylation does not seem to be required for mitochondrial-induced metabolic effects in skeletal muscle cells.
“Interestingly, even if activated, AMPK phosphorylation does not seem to be required for mitochondrial-induced metabolic effects in skeletal muscle cells.”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [259]
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Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance
Pereira, R. O., Tadinada, S. M., Zasadny, F. M., Oliveira, K. J., Pires, K. M. P., Olvera, A., Jeffers, J., Souvenir, R., Mcglauflin, R., Seei, A., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201696179 · Cited by 211 · see citing works
Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action
Ost, M., Coleman, V., Voigt, A., van Schothorst, E. M., Keipert, S., van der Stelt, I., Ringel, S., Graja, A., Ambrosi, T., Kipp, A. P., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2015.11.002 · Cited by 75 · see citing works
Self-citationPotes, Y., Díaz-Luis, A., Bermejo-Millo, J. C., Pérez-Martínez, Z., de Luxán-Delgado, B., Rubio-González, A., Menéndez-Valle, I., Gutiérrez-Rodríguez, J., Solano, J. J., Caballero, B., et al. (2023) · Antioxidants · doi:10.3390/antiox12111962 · Cited by 8 · see citing works
- Authors
- Ost, M., Werner, F., Dokas, J., Klaus, S., & Voigt, A.
- Affiliations
- German Institute of Human Nutrition (DE)
- Corresponding author
- Klaus, Susanne
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-04-14
- Volume
- 9
- Issue
- 4
- Pages
- e94689
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3986237
- OpenAlex
- W2034679839
- Cited by
- 27
- References
- 86
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 1
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- European Commission (244995, 2007–2013, FP7 2007-2013)
- Leibniz-Gemeinschaft (SAW-2013-FBN-3)
- 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
- AMPKα2, skeletal muscle, mitochondrial uncoupling, UCP1, energy expenditure, glucose tolerance, insulin sensitivity, FGF21, muscle degeneration, HSP70, vascular endothelial growth factor, ULK1, mitophagy, mitochondrial respiration, energy balance
- MeSH terms
- Uncoupling Protein 1, Animals, Body Weight, Crosses, Genetic, Fatty Acids, Glucose, Glucose Tolerance Test, Ion Channels, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Phenotype, Phosphorylation, Uncoupling Agents, Muscle, Skeletal, CD36 Antigens, Mitochondrial Proteins, Mice, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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