Differential Myokine Responses to Swimming: Highlighting Meteorin-like (Metrnl) as a Unique Marker of Adaptation

Year 2025, Volume: 15 Issue: 3, 232 - 243, 31.12.2025

Alten Oskay , Özgen Kılıç Erkek , Hande Şenol , Mert Özen , Egem Burcu Ünal , Z. Melek Küçükatay

https://doi.org/10.26650/experimed.1690894

Abstract

Objective: We examined time-dependent changes in levels of Metrnl, IL-7, IL-8, and FSTL1 myokines in mouse gastrocnemius-soleus tissue and plasma samples in response to acute and long-term swimming exercises.
Material and Method: Seventy 8–12-week-old adult male BALB/c mice were divided into control and exercise groups. The exercise group was subjected to either an acute or chronic exercise regime and examined at 0, 3, and 48 h. The acute exercise group completed a 30-min single swimming session. The chronic exercise group completed the 30-min swimming exercise every day, 5 days a week, for 6 weeks. Metrnl, IL-7, IL-8, and FSTL1 levels in the gastrocnemius-soleus muscle complex and plasma samples were measured using ELISA kits.
Results: No changes were observed in the Metrnl, IL-7, IL-8, and FSTL1 levels in the gastrocnemius-soleus muscle complex following acute or 6 weeks of swimming exercise. IL-7, IL-8, and FSTL1 levels did not change in the plasma in response to the exercises. However, plasma Metrnl levels were higher at 3 h after 6 weeks of exercise compared to the control group or the 3-h sample of the acute exercise group.
Conclusion: These findings suggest that unlike FSTL1, IL-7, and IL-8, only Metrnl may play a role in mediating adaptation to long-term exercise in mice.

Keywords

Follistatin-like 1 protein , interleukin-7 , interleukin-8 , meteorin-like protein , swimming

Ethical Statement

This study was approved by the Pamukkale University Animal Experiments Ethics Committee as study number PAUHADYEK-2019/29, dated 22.08.2019 and numbered 2019/06. The institutional and national guide for the care and use of laboratory animals was followed as in “Guide for the Care and Use of Laboratory Animals”.

Supporting Institution

Pamukkale University Scientific Research Projects Coordination Unit

Project Number

2020SABE005

Thanks

This study was supported by the Pamukkale University Scientific Research Projects Coordination Unit (Project No: 2020SABE005).

References

• 1. Hiruma E. Ch 1: Muscles and bones. In: Dugue G, Bruce RT, editors. Osteosarcopenia India: Elsevier; 2022.p.1-18.
• 2. Severinsen MCK, Pedersen BK. Muscle-organ crosstalk: The emerging roles of myokines. Endocr Rev 2020; 41 (4): 594–609. Erratum in: Endocr Rev 2021; 42(1): 97-9.
• 3. Kraemer WJ, Hatfield DL, Comstock BA, Fragala MS, Davitt PM, Cortis C, et al. Influence of HMB supplementation and resistance training on cytokine responses to resistance exercise. J Am Coll Nutr 2014; 33(4): 247-55.
• 4. Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014; 157(6): 1279-91.
• 5. CDC-Centers for Disease Control and Prevention: Chapter 3 - Physiologic responses and long-term adaptations to exercise. Physical activity and health: A report of the surgeon general executive summary (online). (cited 2022 July 03). Available from: URL: https://www.cdc.gov/nccdphp/sgr/chap3.htm.
• 6. Mu S, Huang C, Chen B, Zhao P, Xu H, Zhang W, et al. Sclerostin decreases in regular swimmers after ice swimming and is associated with meteorin-like protein serum levels. Front Physiol 2023; 14: 1210457.
• 7. Algaidi SA, Eldomiaty MA, Elbastwisy YM, Almasry SM, Desouky MK, Elnaggar AM. Effect of voluntary running on expression of myokines in brains of rats with depression. Int J Immunopathol Pharmacol 2019; 33: 2058738419833533.
• 8. Acikel Elmas M, Cakıcı SE, Dur IR, Kozluca I, Arınc M, Binbuga B, et al. Protective effects of exercise on heart and aorta in high-fat diet-induced obese rats. Tissue Cell 2019; 57: 57-65.
• 9. Li KC, Zhang FX, Li CL, Wang F, Yu MY, Zhong YQ, et al. Follistatin-like 1 suppresses sensory afferent transmission by activating Na+, K+-ATPase. Neuron 2011; 69(5): 974-87.
• 10. Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K. Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation 2008; 117(24): 3099-108.
• 11. Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y, et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthasedependent mechanism. J Biol Chem 2008; 283(47): 32802-11.
• 12. Xi Y, Gong DW, Tian Z. FSTL1 as a potential mediator of exercise-induced cardioprotection in post-myocardial infarction rats. Sci Rep 2016; 6: 32424.
• 13. Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone 2015; 80: 115-25.
• 14. Ushach I, Burkhardt AM, Martinez C, Hevezi PA, Gerber PA, Buhren BA, et al. Meteorin-like is a cytokine associated with barrier tissues and alternatively activated macrophages. Clin Immunol 2015; 156(2): 119-27.
• 15. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, et al. CXC chemokines in angiogenesis. J Leukoc Biol 2000; 68(1): 1-8.
• 16. Lira SA, Zalamea P, Heinrich JN, Fuentes ME, Carrasco D, Lewin AC, et al. Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells. J Exp Med 1994; 180(6): 2039-48.
• 17. Bendre MS, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 2003; 33(1): 28-37.
• 18. Rennekampff HO, Hansbrough JF, Kiessig V, Doré C, Sticherling M, Schröder JM. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J Surg Res 2000; 93(1): 41-54.
• 19. Skinner S, Nader E, Stauffer E, Robert M, Boisson C, Cibiel A, et al. Differential impacts of trail and ultra-trail running on cytokine profiles: An observational study. Clin Hemorheol Microcirc 2021; 78(3): 301-10.
• 20. Wang XS, Li BZ, Hu LF, Wen PF, Zhang M, Pan HF, et al. Perspectives of the relationship between IL-7 and autoimmune diseases. Clin Rheumatol 2013; 32(12): 1703-9.
• 21. Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland S, Berg O, et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol 2010; 298(4): C807-16.
• 22. Larsen AI, Aukrust P, Aarsland T, Dickstein K. Effect of aerobic exercise training on plasma levels of tumor necrosis factor alpha in patients with heart failure. Am J Cardiol 2001; 88(7): 805-8.
• 23. Arshadi S, Bakhtiyari S, Haghani K, Valizadeh A. Effects of fenugreek seed extract and swimming endurance training on plasma glucose and cardiac antioxidant enzymes activity in streptozotocin-induced diabetic rats. Osong Public Health Res Perspect 2015; 6(2): 87-93.
• 24. Ravi Kiran T, Subramanyam MV, Asha Devi S. Swim exercise training and adaptations in the antioxidant defense system of myocardium of old rats: relationship to swim intensity and duration. Comp Biochem Physiol B Biochem Mol Biol 2004; 137(2): 187-96.
• 25. Kilic-Erkek O, Caner V, Abban-Mete G, Baris IC, Bor-Kucukatay M. Determination of the pathways of potential muscle damage and regeneration in response to acute and long-term swimming exercise in mice. Life Sci 2021; 272: 119265.
• 26. Ünal EB, Kılıç Erkek Ö, Bor Küçükatay M. An experimental study on investigation of myokine responses to acute and chronic swimming exercise in mice. Turkiye Klinikleri J Med Sci 2024; 44(2): 60-8.
• 27. Scomparin DX, Grassiolli S, Gomes RM, Torrezan R, de Oliveira JC, Gravena C, et al. Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice. Endocr Res 2011; 36(2): 83-90.
• 28. Su X, Yu X, Chen R, Bian W. Swimming improves platelet dysfunction in mice fed with a high-fat diet. Arch Physiol Biochem 2023; 129(1): 198-203.
• 29. Frydelund-Larsen L, Penkowa M, Akerstrom T, Zankari A, Nielsen S, Pedersen BK. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Exp Physiol 2007; 92(1): 233-40.
• 30. Kon M, Tanimura Y, Yoshizato H. Effects of acute endurance exercise on follistatin-like 1 and apelin in the circulation and metabolic organs in rats. Arch Physiol Biochem 2022; 128(5): 1254-8.
• 31. Kon M, Ebi Y, Nakagaki K. Effects of acute sprint interval exercise on follistatin-like 1 and apelin secretions. Arch Physiol Biochem 2021; 127(3): 223-7.
• 32. Schild M, Eichner G, Beiter T, Zügel M, Krumholz-Wagner I, Hudemann J, et al. Effects of acute endurance exercise on plasma protein profiles of endurance-trained and untrained individuals over time. Mediators Inflamm 2016; 2016: 4851935.
• 33. Andersson H, Bøhn SK, Raastad T, Paulsen G, Blomhoff R, Kadi F. Differences in the inflammatory plasma cytokine response following two elite female soccer games separated by a 72-h recovery. Scand J Med Sci Sports 2010; 20(5): 740-7.
• 34. Bote ME, García JJ, Hinchado MD, Ortega E. An exploratory study of the effect of regular aquatic exercise on the function of neutrophils from women with fibromyalgia: role of IL- 8 and noradrenaline. Brain Behav Immun 2014; 39: 107-12.
• 35. Tan J, Guo L. Swimming intervention alleviates insulin resistance and chronic inflammation in metabolic syndrome. Exp Ther Med 2019; 17(1): 57-62.
• 36. Li ZY, Zheng SL, Wang P, Xu TY, Guan YF, Zhang YJ, et al. Subfatin is a novel adipokine and unlike Meteorin in adipose and brain expression. CNS Neurosci Ther 2014; 20(4): 344-54.
• 37. Zheng SL, Li ZY, Song J, Liu JM, Miao CY. Metrnl: a secreted protein with new emerging functions. Acta Pharmacol Sin 2016; 37(5): 571-9.
• 38. Bae JY, Woo J, Kang S, Shin KO. Effects of detraining and retraining on muscle energy-sensing network and meteorin-like levels in obese mice. Lipids Health Dis 2018; 17(1): 97.
• 39. Bonfante ILP, Duft RG, Mateus KCDS, Trombeta JCDS, Finardi EAR, Ramkrapes APB, et al. Acute/chronic responses of combined training on serum pro-thermogenic/anti-inflammatory inducers and its relation with fed and fasting state in overweight type 2 diabetic individuals. Front Physiol 2022; 12: 736244.
• 40. Jung TW, Lee SH, Kim HC, Bang JS, Abd El-Aty AM, Hacımüftüoğlu A, et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp Mol Med 2018; 50(9): 1-11.
• 41. Li Z, Gao Z, Sun T, Zhang S, Yang S, Zheng M, Shen H. Meteorin-like/ Metrnl, a novel secreted protein implicated in inflammation, immunology, and metabolism: A comprehensive review of preclinical and clinical studies. Front Immunol 2023; 14: 1098570.
• 42. Kironenko TA, Milovanova KG, Zakharova AN, Sidorenko SV, Klimanova EA, Dyakova EY, et al. Effect of dynamic and static load on the concentration of myokines in the blood plasma and content of sodium and potassium in mouse skeletal muscles. Biochemistry (Mosc) 2021; 86(3): 370-81.
• 43. Pedersen BK, Akerström TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985) 2007; 103(3): 1093-8.
• 44. Landers-Ramos RQ, Jenkins NT, Spangenburg EE, Hagberg JM, Prior SJ. Circulating angiogenic and inflammatory cytokine responses to acute aerobic exercise in trained and sedentary young men. Eur J Appl Physiol 2014; 114(7): 1377-84.
• 45. Dorneles GP, Haddad DO, Fagundes VO, Vargas BK, Kloecker A, Romão PR, et al. High intensity interval exercise decreases IL-8 and enhances the immunomodulatory cytokine interleukin-10 in lean and overweight-obese individuals. Cytokine 2016; 77: 1-9.
• 46. Kim MS, Lim WK, Park RK, Shin T, Yoo YH, Hong SH, et al. Involvement of mitogen-activated protein kinase and NF-kappaB activation in Ca2+-induced IL-8 production in human mast cells. Cytokine 2005; 32(5): 226-33.
• 47. Chan MH, Carey AL, Watt MJ, Febbraio MA. Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability. Am J Physiol Regul Integr Comp Physiol 2004; 287(2): R322-7.
• 48. Sawa Y, Arima Y, Ogura H, Kitabayashi C, Jiang JJ, Fukushima T, et al. Hepatic interleukin-7 expression regulates T cell responses. Immunity 2009; 30(3): 447-57.
• 49. García JJ, Bote E, Hinchado MD, Ortega E. A single session of intense exercise improves the inflammatory response in healthy sedentary women. J Physiol Biochem 2011; 67(1): 87-94.
• 50. Ahn N, Kim K. Effects of aerobic and resistance exercise on myokines in high fat diet-induced middle-aged obese rats. Int J Environ Res Public Health 2020; 17(8): 2685.
• 51. Sylvia M, Li VS, Buffing AA, van Es JH, van den Born M, van der Velden S, et al. The BMP antagonist follistatin- like 1 is required for skeletal and lung organogenesis. PLoS One 2011; 6(8): e22616.
• 52. Miyamae T, Marinov AD, Sowders D, Wilson DC, Devlin J, Boudreau R, et al. Follistatin-like protein-1 is a novel proinflammatory molecule. J Immunol 2006; 177(7): 4758-62.
• 53. Görgens SW, Raschke S, Holven KB, Jensen J, Eckardt K, Eckel J. Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells. Arch Physiol Biochem 2013; 119(2): 75-80.
• 54. Xu X, Zhang T, Mokou M, Li L, Li P, Song J, et al. Follistatin-like 1 as a novel adipomyokine related to insulin resistance and physical activity. J Clin Endocrinol Metab 2020; 105(12): dgaa629.
• 55. Poole GW, Crepin BJ, Sevigny M. Physiological characteristics of elite synchronized swimmers. Can J Appl Sport Sci 1980; 5(3): 156-60.
• 56. Barrero A, Erola P, Bescós R. Energy balance of triathletes during an ultraendurance event. Nutrients 2014; 7 (1): 209-22.
• 57. Barbosa TM, Bragada JA, Reis VM, Marinho DA, Carvalho C, Silva AJ. Energetics and biomechanics as determining factors of swimming performance: updating the state of the art. J Sci Med Sport 2010; 13(2): 262-9.
• 58. Lambert CP, Flynn MG, Braun WA, Boardley DJ. The effects of swimming and running on energy intake during 2 hours of recovery. J Sports Med Phys Fitness. 1999; 39(4): 348-54.
• 59. Börzsei D, Szabó R, Hoffmann A, Harmath A, Sebestyén J, Osman J, et al. Multiple applications of different exercise modalities with rodents. Oxid Med Cell Longev 2021; 2021: 3898710.