Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake
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Abstract
Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.
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- Authors
- Kjærgaard, J., Lindqvist, C. B., Quesada, J. P., Jessen, S., Schlabs, F., Ehrlich, A. M., Yonamine, C. Y., García-Ureña, M., Schmalbruch, J. H., Small, L., Thomassen, M., Lemminger, A. K., Eibye, K., Gonzalez-Franquesa, A., Stidsen, J. V., Højlund, K., Zierath, J. R., Kilpeläinen, T. O., Bangsbo, J., Treebak, J. T., Hostrup, M., & Deshmukh, A. S.
- Affiliations
- University of Copenhagen (DK)
- Odense University Hospital (DK)
- University of Southern Denmark (DK)
- Corresponding author
- Hostrup, Morten
- Deshmukh, Atul S.
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2025-06
- Volume
- 6
- Issue
- 6
- Pages
- 102163
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC12208332
- OpenAlex
- W4411090554
- Cited by
- 11
- References
- 9
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 1
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novo Nordisk Foundation (NNF19SA0059305, NNF18CC0034900, NNF15OC0015986, NNF22OC0074128)
- Region Syddanmark
- Savvaerksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat
- Københavns Universitet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- skeletal muscle glucose uptake, insulin signaling, p90 ribosomal S6 kinase, protein phosphorylation, insulin resistance, insulin sensitivity, therapeutic target
- MeSH terms
- Adult, Animals, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Phosphoproteins, Phosphorylation, Signal Transduction, Exercise, Muscle, Skeletal, Ribosomal Protein S6 Kinases, 90-kDa, Proteomics, Mice
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