The DOI matches its Crossref record; 49 of the 50 references it cites were found in a registry or an index.
Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates
Open accessAbstract
Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Moreover, the phosphorylation of human BAG3 on Thr285 and Ser 289 decreases in response to endurance exercise (61).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [61]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Skyline: an open source document editor for creating and analyzing targeted proteomics experiments
MacLean, B., Tomazela, D. M., Shulman, N., Chambers, M., Finney, G. L., Frewen, B., Kern, R., Tabb, D. L., Liebler, D. C., & MacCoss, M. J. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq054 · Cited by 4,697
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849
Gillet, L. C., Navarro, P., Tate, S., Röst, H., Selevsek, N., Reiter, L., Bonner, R., & Aebersold, R. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o111.016717 · Cited by 2,877
Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation
Egan, B., & Zierath, J. R. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.012 · Cited by 2,084
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,672
Hornbeck, P. V., Kornhauser, J. M., Tkachev, S., Zhang, B., Skrzypek, E., Murray, B. W., Latham, V. M., & Sullivan, M. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1122 · Cited by 1,636
Antioxidants prevent health-promoting effects of physical exercise in humans
Ristow, M., Zarse, K., Oberbach, A., Klöting, N., Birringer, M., Kiehntopf, M., Stumvoll, M., Kahn, C. R., & Blüher, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903485106 · Cited by 1,582
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501
Integrative Biology of Exercise
Hawley, J. A., Hargreaves, M., Joyner, M. J., & Zierath, J. R. (2014) · Cell · doi:10.1016/j.cell.2014.10.029 · Cited by 1,152
Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893
STIM proteins: dynamic calcium signal transducers
Soboloff, J., Rothberg, B. S., Madesh, M., & Gill, D. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3414 · Cited by 661
AMPK—Sensing Energy while Talking to Other Signaling Pathways
Hardie, D. G. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.013 · Cited by 597
Na + -K + Pump Regulation and Skeletal Muscle Contractility
Clausen, T. (2003) · Physiological Reviews · doi:10.1152/physrev.00011.2003 · Cited by 582
mProphet: automated data processing and statistical validation for large-scale SRM experiments
Reiter, L., Rinner, O., Picotti, P., Hüttenhain, R., Beck, M., Brusniak, M.-Y., Hengartner, M. O., & Aebersold, R. (2011) · Nature Methods · doi:10.1038/nmeth.1584 · Cited by 532
AMPK and the biochemistry of exercise: implications for human health and disease
Richter, E. A., & Ruderman, N. B. (2009) · Biochemical Journal · doi:10.1042/bj20082055 · Cited by 481
Self-citationMolecular mechanism of action of metformin: old or new insights?
Rena, G., Pearson, E. R., & Sakamoto, K. (2013) · Diabetologia · doi:10.1007/s00125-013-2991-0 · Cited by 479
Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits
Neufer, P. D., Bamman, M. M., Muoio, D. M., Bouchard, C., Cooper, D. M., Goodpaster, B. H., Booth, F. W., Kohrt, W. M., Gerszten, R. E., Mattson, M. P., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.011 · Cited by 474
Dynamic Adipocyte Phosphoproteome Reveals that Akt Directly Regulates mTORC2
Humphrey, S. J., Yang, G., Yang, P., Fazakerley, D. J., Stöckli, J., Yang, J. Y. H., & James, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.010 · Cited by 412
Self-citationO'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., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105062108 · Cited by 406
Self-citationNetworKIN: a resource for exploring cellular phosphorylation networks
Linding, R., Jensen, L. J., Pasculescu, A., Olhovsky, M., Colwill, K., Bork, P., Yaffe, M. B., & Pawson, T. J. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm902 · Cited by 395
Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues
Lundby, A., Secher, A., Lage, K., Nordsborg, N. B., Dmytriyev, A., Lundby, C., & Olsen, J. V. (2012) · Nature Communications · doi:10.1038/ncomms1871 · Cited by 343
PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis
Djouder, N., Tuerk, R. D., Suter, M., Chiabotti, P. S., Thali, R. F., Scholz, R., Vaahtomeri, K., Auchli, Y., Rechsteiner, H., Brunisholz, R., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.339 · Cited by 285
Invited Review: Intracellular signaling in contracting skeletal muscle
Sakamoto, K., & Goodyear, L. J. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00167.2002 · Cited by 260
Chemical Genetic Screen for AMPKα2 Substrates Uncovers a Network of Proteins Involved in Mitosis
Banko, M. R., Allen, J. J., Schaffer, B. E., Wilker, E., Tsou, P., White, J. L., Villén, J., Wang, B., Kim, S. R., Sakamoto, K., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.11.005 · Cited by 252
Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle
Widegren, U., Jiang, X. J., Krook, A., Chibalin, A., Björnholm, M., Tally, M., Roth, R. A., Henriksson, J., Wallberg‐Henriksson, H., & Zierath, J. R. (1998) · The FASEB Journal · doi:10.1096/fasebj.12.13.1379 · Cited by 248
Initial Quantitative Proteomic Map of 28 Mouse Tissues Using the SILAC Mouse
Geiger, T., Velic, A., Macek, B., Lundberg, E., Kampf, C., Nagaraj, N., Uhlen, M., Cox, J., & Mann, M. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.024919 · Cited by 235
Exercise and insulin cause GLUT-4 translocation in human skeletal muscle
Thorell, A., Hirshman, M. F., Nygren, J., Jorfeldt, L., Wojtaszewski, J. F. P., Dufresne, S. D., Horton, E. S., Ljungqvist, O. H., & Goodyear, L. J. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.4.e733 · Cited by 193
Self-citationEngholm‐Keller, K., Birck, P. K., Størling, J., Pociot, F., Mandrup-Poulsen, T. R., & Larsen, M. R. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.08.007 · Cited by 174
Zhao, X., León, I. R., Bak, S. Y., Mogensen, M., Wrzesinski, K., Højlund, K., & Jensen, O. N. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.000299 · Cited by 169
Ducommun, S., Deak, M., Sumpton, D., Ford, R. J., Núñez Galindo, A., Kussmann, M., Viollet, B., Steinberg, G. R., Foretz, M., Dayon, L., et al. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.02.008 · Cited by 167
Mitochondrial AKAP121 Links cAMP and src Signaling to Oxidative Metabolism
Livigni, A., Scorziello, A., Agnese, S., Adornetto, A., Carlucci, A., Garbi, C., Castaldo, I., Annunziato, L., Avvedimento, E. V., & Feliciello, A. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-09-0827 · Cited by 157
AMPK‐independent pathways regulate skeletal muscle fatty acid oxidation
Dzamko, N., Schertzer, J. D., Ryall, J. G., Steel, R., Macaulay, S. L., Wee, S., Chen, Z., Michell, B. J., Oakhill, J. S., Watt, M. J., et al. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.159814 · Cited by 147
Mitochondria: A kinase anchoring protein 1, a signaling platform for mitochondrial form and function
Merrill, R. A., & Strack, S. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.12.012 · Cited by 100
Maarbjerg, S., Jørgensen, S. B., Rose, A. J., Jeppesen, J. F., Jensen, T. E., Treebak, J. T., Birk, J. B., Schjerling, P., Wojtaszewski, J. F. P., & Richter, E. A. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90653.2008 · Cited by 95
Self-citationHøjlund, K., Bowen, B. P., Hwang, H., Flynn, C. R., Madireddy, L., Geetha, T., Langlais, P. R., Meyer, C., Mandarino, L. J., & Yi, Z. (2009) · Journal of Proteome Research · doi:10.1021/pr9007267 · Cited by 85
Fentz, J., Kjøbsted, R., Birk, J. B., Jordy, A. B., Jeppesen, J. F., Thorsen, K., Schjerling, P., Kiens, B., Jessen, N., Viollet, B., et al. (2015) · The FASEB Journal · doi:10.1096/fj.14-266650 · Cited by 84
Self-citationRegulation of Glycogen Synthase Kinase-3 in Human Skeletal Muscle
Wojtaszewski, J. F. P., Nielsen, P., Kiens, B., & Richter, E. A. (2001) · Diabetes · doi:10.2337/diabetes.50.2.265 · Cited by 83
Self-citationLKB1 Regulates Lipid Oxidation During Exercise Independently of AMPK
Jeppesen, J. F., Maarbjerg, S., Jordy, A. B., Fritzen, A. M., Pehmøller, C. K., Sylow, L., Serup, A. K., Jessen, N., Thorsen, K., Prats, C., et al. (2013) · Diabetes · doi:10.2337/db12-1160 · Cited by 82
Self-citationRedefining the role of mitochondria in exercise: a dynamic remodeling
Hai, B., Zhang, Y., & Ji, L. L. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05618.x · Cited by 67
Marrades, M. P., González‐Muniesa, P., Martínez, J. A., & Moreno-Aliaga, M. J. (2010) · Obesity Facts · doi:10.1159/000321451 · Cited by 57
Knight, J. D. R., Tian, R., Lee, R., Wang, F., Beauvais, A., Zou, H., Megeney, L. A., Gingras, A., Pawson, T. J., Figeys, D., et al. (2012) · Skeletal Muscle · doi:10.1186/2044-5040-2-5 · Cited by 51
Chaudhuri, R., Sadrieh, A., Hoffman, N. J., Parker, B. L., Humphrey, S. J., Stöckli, J., Hill, A. P., James, D. E., & Yang, J. Y. H. (2015) · BMC Genomics · doi:10.1186/s12864-015-1820-x · Cited by 28
Self-citationScaffold State Switching Amplifies, Accelerates, and Insulates Protein Kinase C Signaling
Greenwald, E. C., Redden, J. M., Dodge‐Kafka, K. L., & Saucerman, J. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.497941 · Cited by 27
Identification and characterization of D-AKAP1 as a major adipocyte PKA and PP1 binding protein
Bridges, D., MacDonald, J. A., Wadzinski, B. E., & Moorhead, G. B. G. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.05.138 · Cited by 26
Klaus, A., Polge, C., Zorman, S., Auchli, Y., Brunisholz, R., & Schlattner, U. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.03.040 · Cited by 19
Bennetzen, M. V., Cox, J., Mann, M., & Andersen, J. (2012) · Journal of Proteome Research · doi:10.1021/pr300016e · Cited by 18
Cited by
Sorted by citations
AMPK: guardian of metabolism and mitochondrial homeostasis
Herzig, S., & Shaw, R. J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.95 · Cited by 4,192
AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance
Garcia, D., & Shaw, R. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.032 · Cited by 2,061
Pattern recognition receptors in health and diseases
Li, D., & Wu, M. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00687-0 · Cited by 1,961
Mitochondrial dynamics in health and disease: mechanisms and potential targets
Chen, W., Zhao, H., & Li, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01547-9 · Cited by 1,306
Skeletal muscle energy metabolism during exercise
Hargreaves, M., & Spriet, L. L. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0251-4 · Cited by 1,408
Metadata
- Authors
- Hoffman, N. J., Parker, B. L., Chaudhuri, R., Fisher-Wellman, K. H., Kleinert, M., Humphrey, S. J., Yang, P., Holliday, M., Trefely, S., Fazakerley, D. J., Stöckli, J., Burchfield, J. G., Jensen, T. E., Jothi, R., Kiens, B., Wojtaszewski, J. F. P., Richter, E. A., & James, D. E.
- Affiliations
- The University of Sydney (AU)
- University of Copenhagen (DK)
- Garvan Institute of Medical Research (AU)
- National Institutes of Health (US)
- Corresponding author
- James, David E.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 22
- Issue
- 5
- Pages
- 922-935
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4635038
- OpenAlex
- W1839260472
- Cited by
- 426
- References
- 50
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 45 · 2023: 37 · 2022: 47 · 2021: 46 · 2020: 45 · 2019: 50 · 2018: 32 · 2017: 30 · 2016: 25 · 2015: 4
- FWCI
- 13.18
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-11-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Bank (Australian Catholic University) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF15OC0015182, NNF14OC0012009, NNF14OC0012319)
- National Institutes of Health
- National Institute of Environmental Health Sciences (ZIAES102625)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
- Keywords
- skeletal muscle, protein phosphorylation, AKAP1, mitochondrial respiration, high-intensity exercise, phosphosites, kinase substrates, energy metabolism, insulin sensitivity, phosphoproteomics
- MeSH terms
- Machine Learning, Adult, Energy Metabolism, Humans, Male, Mitochondria, Phosphoproteins, Phosphorylation, Physical Conditioning, Animal, Substrate Specificity, Signal Transduction, Exercise, Muscle, Skeletal, A Kinase Anchor Proteins, 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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
