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  3. Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake

Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake

  • Cell Rep Med. 2025 Jun 17;6(6):102163. doi: 10.1016/j.xcrm.2025.102163.
Jeppe Kjærgaard 1,  Cecilie B Lindqvist 1,  Júlia Prats Quesada 1,  Søren Jessen 2,  Farina Schlabs 1,  Amy M Ehrlich 1,  Caio Y Yonamine 1,  Mario García-Ureña 1,  Johann H Schmalbruch 1,  Lewin Small 1,  Martin Thomassen 2,  Anders Krogh Lemminger 2,  Kasper Eibye 2,  Alba Gonzalez-Franquesa 1,  Jacob V Stidsen 3,  Kurt Højlund 4,  Juleen R Zierath 5,  Tuomas O Kilpeläinen 1,  Jens Bangsbo 2,  Jonas T Treebak 1,  Morten Hostrup 6,  Atul S Deshmukh 7
Affiliations

Affiliations

  • 1 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 2 The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
  • 3 Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark.
  • 4 Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, University of Southern Denmark, Odense C, Denmark.
  • 5 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
  • 6 The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark. Electronic address: mhostrup@nexs.ku.dk.
  • 7 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: atul.deshmukh@sund.ku.dk.
PMID: 40482643 DOI: 10.1016/j.xcrm.2025.102163
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.

Keywords

REPS1; RSK; exercise; glucose metabolism; insulin; phosphoproteomics; skeletal muscle signaling.

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