Cited by 426Metabolism, Diabetes, and CancerMuscle metabolism and nutritionCardiovascular and exercise physiology

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Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates

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Hoffman, Nolan J., Parker, Benjamin L., Chaudhuri, Rima, Fisher-Wellman, Kelsey H., Kleinert, Maximilian, Humphrey, Sean J., Yang, Pengyi, Holliday, Mira, Trefely, Sophie, Fazakerley, Daniel J., Stöckli, Jacqueline, Burchfield, James G., Jensen, Thomas E., Jothi, Raja, Kiens, Bente, Wojtaszewski, Jørgen F.P., Richter, Erik A., James, David E.·2015·Cell Metabolism

DOI 10.1016/j.cmet.2015.09.001PMC PMC4635038

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Abstract

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.

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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: Hoffman, Nolan J.
Parker, Benjamin L.
Kleinert, Maximilian
Humphrey, Sean J.
Yang, Pengyi
Holliday, Mira
Trefely, Sophie
Fazakerley, Daniel J.
Stöckli, Jacqueline
Burchfield, James G.
Jensen, Thomas E.
Kiens, Bente
Wojtaszewski, Jørgen F.P.
Richter, Erik A.
James, David E.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2015-11
Volume: 22
Issue: 5
Pages: 922-935
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2015.09.001
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
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

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Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates

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