Acute exercise increases syndecan-1 and -4 serum concentrations

  • Sindre Lee
  • Svein O. Kolset
  • Kåre I. Birkeland
  • Christian A. Drevon
  • Trine M. ReineEmail author
Original Article


The effects of acute and long-term exercise on syndecans and the relationship to insulin sensitivity are not fully explored. We aimed to examine the effects of acute and 12 weeks of exercise on (1) serum levels of syndecan-1 and -4, (2) gene expression related to syndecan synthesis and modification in skeletal muscle and adipose tissue, and (3) the relationship to insulin sensitivity. Sedentary men with (n = 13) or without (n = 13) dysglycemia underwent two 45 min acute bicycle tests interspersed by 12 weeks of exercise intervention. Euglycemic hyperinsulinemic clamp and mRNA-sequencing of skeletal muscle and adipose tissue biopsies were performed before and after intervention. Serum syndecan-1 and -4 levels were quantified before, immediately after and 2 h after bicycling. Syndecan-1 and -4 serum concentrations increased in response to acute physical exercise. Baseline syndecan-4 but not syndecan-1 concentrations were higher in dysglycemic compared to normoglycemic men, and correlated to change in insulin sensitivity, but did not change during the 12 weeks exercise intervention. Only syndecan-4 was expressed in skeletal muscle and adipose tissue. Adipose tissue mRNA levels of transcripts affecting syndecan structure and shedding were upregulated in dysglycemia, and muscle mRNA responded to long-term physical activity. The increase in serum syndecan-1 and -4 due to acute exercise suggest increased syndecan shedding and disruption of glycocalyx in response to increased blood flow. The higher syndecan-4 baseline serum levels in dysglycemia, association to insulin sensitivity, and changes in mRNA transcripts may suggest syndecan-4 involvement in muscle and adipose tissue response to exercise.


Exercise Syndecans Syndecan-shedding Endothelial glycocalyx Dysglycemia Insulin sensitivity 



This work was supported by grants from the Institute of Basic Medical Sciences, UiO, Johan Throne-Holst Foundation for Nutrition Research, Freia Medical Research Foundation, the “Functional Genomics” and “Infrastructure” programs of the Research Council of Norway and the Southeastern Regional Health Authorities.

We thank Anne Randi Enget, Ansgar Heck and Birgitte Nellemann for taking the biopsies, and Tor I Gloppen, Torstein Dalen, Håvard Moen, Marius A Dahl, Guro Grøthe, Egil Johansen, Katrine A Krog, Øyvind Skattebo, Daniel S Tangen, Kristoffer K Jensen, Hans K Stadheim, and Eirin Rise for conducting the human strength and endurance intervention (MyoGlu) under supervision of Professor Jørgen Jensen. Sequencing was performed by PhD Gregor Gilfilan at the Norwegian Sequencing Centre ( supported by the Research Council of Norway and the South-eastern Regional Health Authorities.

Author’s contributions

SL analyzed and prepared the data. SL, CAD and TMR interpreted the data and wrote the manuscript. KIB and CAD designed, planned and received grant funding for MyoGlu. All authors reviewed and revised the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the reported research.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10719_2019_9869_MOESM1_ESM.docx (63 kb)
ESM 1 (DOCX 63 kb)


  1. 1.
    Couchman, J.R.: Transmembrane signaling proteoglycans. Annu. Rev. Cell Dev. Biol. 26, 89–114 (2010). CrossRefGoogle Scholar
  2. 2.
    Pisconti, A., Bernet, J.D., Olwin, B.B.: Syndecans in skeletal muscle development, regeneration and homeostasis. MLTJ. 2(1), 1–9 (2012)Google Scholar
  3. 3.
    Xian, X., Gopal, S., Couchman, J.R.: Syndecans as receptors and organizers of the extracellular matrix. Cell Tissue Res. 339(1), 31–46 (2010). CrossRefGoogle Scholar
  4. 4.
    De Rossi, G., Whiteford, J.R.: Syndecans in angiogenesis and endothelial cell biology. Biochem. Soc. Trans. 42(6), 1643–1646 (2014). CrossRefGoogle Scholar
  5. 5.
    Chung, H., Multhaupt, H.A., Oh, E.S., Couchman, J.R.: Minireview: Syndecans and their crucial roles during tissue regeneration. FEBS Lett. 590(15), 2408–2417 (2016). CrossRefGoogle Scholar
  6. 6.
    Ronning, S.B., Carlson, C.R., Stang, E., Kolset, S.O., Hollung, K., Pedersen, M.E.: Syndecan-4 regulates muscle differentiation and is internalized from the plasma membrane during Myogenesis. PLoS One. 10(6), e0129288 (2015). CrossRefGoogle Scholar
  7. 7.
    Cornelison, D.D., Filla, M.S., Stanley, H.M., Rapraeger, A.C., Olwin, B.B.: Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev. Biol. 239(1), 79–94 (2001). CrossRefGoogle Scholar
  8. 8.
    Reitsma, S., Slaaf, D.W., Vink, H., van Zandvoort, M.A., oude Egbrink, M.G.: The endothelial glycocalyx: composition, functions, and visualization. Arch Eur J Physiol. 454(3), 345–359 (2007). CrossRefGoogle Scholar
  9. 9.
    Mitra, R., O'Neil, G.L., Harding, I.C., Cheng, M.J., Mensah, S.A., Ebong, E.E.: Glycocalyx in atherosclerosis-relevant endothelium function and as a therapeutic target. Curr. Atheroscler. Rep. 19(12), 63 (2017). CrossRefGoogle Scholar
  10. 10.
    Lindahl, U., Kusche-Gullberg, M., Kjellén, L.: Regulated diversity of heparan sulfate. J. Biol. Chem. 273(39), 24979 (1998)CrossRefGoogle Scholar
  11. 11.
    Manon-Jensen, T., Itoh, Y., Couchman, J.R.: Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 277(19), 3876–3889 (2010). CrossRefGoogle Scholar
  12. 12.
    Becker, B.F., Chappell, D., Bruegger, D., Annecke, T., Jacob, M.: Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc. Res. 87(2), 300–310 (2010). CrossRefGoogle Scholar
  13. 13.
    Lemkes, B.A., Nieuwdorp, M., Hoekstra, J.B., Holleman, F.: The glycocalyx and cardiovascular disease in diabetes: should we judge the endothelium by its cover? Diabetes Technol. Ther. 14(Suppl 1), S3–S10 (2012). CrossRefGoogle Scholar
  14. 14.
    Boels, M.G., Avramut, M.C., Koudijs, A., Dane, M.J., Lee, D.H., van der Vlag, J., Koster, A.J., van Zonneveld, A.J., van Faassen, E., Grone, H.J., van den Berg, B.M., Rabelink, T.J.: Atrasentan reduces albuminuria by restoring the glomerular endothelial Glycocalyx barrier in diabetic nephropathy. Diabetes. 65, 2429–2439 (2016). CrossRefGoogle Scholar
  15. 15.
    Vuong, T.T., Reine, T.M., Sudworth, A., Jenssen, T., Kolset, S.O.: Syndecan-4 is a major syndecan in primary human endothelial cells in vitro, modulated by inflammatory stimuli and involved in wound healing. J. Histochem. Cytochem. 63(4), 280–292 (2015).
  16. 16.
    Schott, U., Solomon, C., Fries, D., Bentzer, P.: The endothelial glycocalyx and its disruption, protection and regeneration: a narrative review. Scandinavian journal of trauma, resuscitation and emergency medicine. 24, 48 (2016). CrossRefGoogle Scholar
  17. 17.
    Svennevig, K., Hoel, T., Thiara, A., Kolset, S., Castelheim, A., Mollnes, T., Brosstad, F., Fosse, E., Svennevig, J.: Syndecan-1 plasma levels during coronary artery bypass surgery with and without cardiopulmonary bypass. Perfusion. 23(3), 165–171 (2008). CrossRefGoogle Scholar
  18. 18.
    Svennevig, K., Kolset, S.O., Bangstad, H.J.: Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients. Diabetologia. 49(9), 2214–2216 (2006). CrossRefGoogle Scholar
  19. 19.
    Reine, T.M., Kolseth, I.B., Meen, A.J., Lindahl, J.P., Jenssen, T.G., Reinholt, F.P., Zaia, J., Shao, C., Hartmann, A., Kolset, S.O.: Effects of restoring normoglycemia in type 1 diabetes on inflammatory profile and renal extracellular matrix structure after simultaneous pancreas and kidney transplantation. Diabetes Res. Clin. Pract. 107(1), 46–53 (2015). CrossRefGoogle Scholar
  20. 20.
    Solbu, M.D., Kolset, S.O., Jenssen, T.G., Wilsgaard, T., Løchen, M.-L., Mathiesen, E.B., Melsom, T., Eriksen, B.O., Reine, T.M.: Gender Differences in the Association of Syndecan-4 with Myocardial Infarction. The Population-Based Tromsø Study. Atherosclerosis. doi:, 2018
  21. 21.
    Dogne, S., Flamion, B., Caron, N.: Endothelial Glycocalyx as a shield against diabetic vascular complications: involvement of Hyaluronan and hyaluronidases. Arterioscler. Thromb. Vasc. Biol. 38(7), 1427–1439 (2018). CrossRefGoogle Scholar
  22. 22.
    Codella, R., Ialacqua, M., Terruzzi, I., Luzi, L.: May the force be with you: why resistance training is essential for subjects with type 2 diabetes mellitus without complications. Endocrine. 62, 14–25 (2018). CrossRefGoogle Scholar
  23. 23.
    Bird, S.R., Hawley, J.A.: Update on the effects of physical activity on insulin sensitivity in humans. BMJ Open Sport Exerc. Med. 2(1), e000143 (2016). CrossRefGoogle Scholar
  24. 24.
    Richter, E.A., Hargreaves, M.: Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol. Rev. 93(3), 993–1017 (2013). CrossRefGoogle Scholar
  25. 25.
    Hjorth, M., Norheim, F., Meen, A.J., Pourteymour, S., Lee, S., Holen, T., Jensen, J., Birkeland, K.I., Martinov, V.N., Langleite, T.M., Eckardt, K., Drevon, C.A., Kolset, S.O.: The effect of acute and long-term physical activity on extracellular matrix and serglycin in human skeletal muscle. Physiological Reports. 3(8), (2015).
  26. 26.
    Langleite, T.M., Jensen, J., Norheim, F., Gulseth, H.L., Tangen, D.S., Kolnes, K.J., Heck, A., Storas, T., Grothe, G., Dahl, M.A., Kielland, A., Holen, T., Noreng, H.J., Stadheim, H.K., Bjornerud, A., Johansen, E.I., Nellemann, B., Birkeland, K.I., Drevon, C.A.: Insulin sensitivity, body composition and adipose depots following 12 w combined endurance and strength training in dysglycemic and normoglycemic sedentary men. Arch. Physiol. Biochem. 122(4), 167–179 (2016). CrossRefGoogle Scholar
  27. 27.
    Lee, S., Norheim, F., Langleite, T.M., Noreng, H.J., Storas, T.H., Afman, L.A., Frost, G., Bell, J.D., Thomas, E.L., Kolnes, K.J., Tangen, D.S., Stadheim, H.K., Gilfillan, G.D., Gulseth, H.L., Birkeland, K.I., Jensen, J., Drevon, C.A., Holen, T.: Effect of energy restriction and physical exercise intervention on phenotypic flexibility as examined by transcriptomics analyses of mRNA from adipose tissue and whole body magnetic resonance imaging. Physiological Reports. 4(21), (2016).
  28. 28.
    Li, Y., Lee, S., Langleite, T., Norheim, F., Pourteymour, S., Jensen, J., Stadheim, H.K., Storas, T.H., Davanger, S., Gulseth, H.L., Birkeland, K.I., Drevon, C.A., Holen, T.: Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention. Physiological Reports. 2(11), (2014).
  29. 29.
    Norheim, F., Hjorth, M., Langleite, T.M., Lee, S., Holen, T., Bindesboll, C., Stadheim, H.K., Gulseth, H.L., Birkeland, K.I., Kielland, A., Jensen, J., Dalen, K.T., Drevon, C.A.: Regulation of angiopoietin-like protein 4 production during and after exercise. Physiological Reports. 2(8), (2014).
  30. 30.
    Majerczak, J., Duda, K., Chlopicki, S., Bartosz, G., Zakrzewska, A., Balcerczyk, A., Smolenski, R.T., Zoladz, J.A.: Endothelial glycocalyx integrity is preserved in young, healthy men during a single bout of strenuous physical exercise. Physiol. Res. 65(2), 281–291 (2016)Google Scholar
  31. 31.
    Majerczak, J., Grandys, M., Duda, K., Zakrzewska, A., Balcerczyk, A., Kolodziejski, L., Szymoniak-Chochol, D., Smolenski, R.T., Bartosz, G., Chlopicki, S., Zoladz, J.A.: Moderate-intensity endurance training improves endothelial glycocalyx layer integrity in healthy young men. Exp. Physiol. 102(1), 70–85 (2017). CrossRefGoogle Scholar
  32. 32.
    Cornelison, D.D., Wilcox-Adelman, S.A., Goetinck, P.F., Rauvala, H., Rapraeger, A.C., Olwin, B.B.: Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Genes Dev. 18(18), 2231–2236 (2004). CrossRefGoogle Scholar
  33. 33.
    Fitzgerald, M.L., Wang, Z., Park, P.W., Murphy, G., Bernfield, M.: Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J. Cell Biol. 148(4), 811–824 (2000)CrossRefGoogle Scholar
  34. 34.
    Kreuger, J., Spillmann, D., Li, J.P., Lindahl, U.: Interactions between heparan sulfate and proteins: the concept of specificity. J. Cell Biol. 174(3), 323–327 (2006). CrossRefGoogle Scholar
  35. 35.
    Gotte, M.: Syndecans in inflammation. FASEB J. 17(6), 575–591 (2003). CrossRefGoogle Scholar
  36. 36.
    Lippi, G., Salvagno, G.L., Tarperi, C., Gelati, M., Montagnana, M., Danese, E., Festa, L., Sanchis-Gomar, F., Favaloro, E.J., Schena, F.: Prothrombotic state induced by middle-distance endurance exercise in middle-aged athletes. Semin. Thromb. Hemost. 44, 747–755 (2018). CrossRefGoogle Scholar
  37. 37.
    Keller-Pinter, A., Szabo, K., Kocsis, T., Deak, F., Ocsovszki, I., Zvara, A., Puskas, L., Szilak, L., Dux, L.: Syndecan-4 influences mammalian myoblast proliferation by modulating myostatin signalling and G1/S transition. FEBS Lett. 592, 3139–3151 (2018). CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nutrition, Institute of Basic Medical Sciences, Faculty of MedicineUniversity of OsloOsloNorway
  2. 2.Department of Endocrinology, Morbid Obesity and Preventive MedicineOslo University HospitalOsloNorway
  3. 3.Institute of Clinical Medicine, Faculty of medicineUniversity of OsloOsloNorway
  4. 4.Institute for Cancer Genetics and InformaticsOslo University HospitalOsloNorway

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