Skip to main content

Advertisement

SpringerLink
Log in

IL-15 expression increased in response to treadmill running and inhibited endoplasmic reticulum stress in skeletal muscle in rats

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Interleukin 15 (IL-15) has recently been proposed as a circulating myokine involved in glucose uptake and utilization in skeletal muscle. However, the role and mechanism of IL-15 in exercise improving insulin resistance (IR) is unclear. Here, we investigated the alteration in expression of IL-15 and IL-15 receptor α (IL-15Rα) in skeletal muscle during treadmill running in rats with IR induced by a high-fat diet (HFD) and elucidated the mechanism of the anti-IR effects of IL-15. At 20 weeks of HFD, rats showed severe IR, with increased levels of fasting blood sugar and plasma insulin, impaired glucose tolerance, and reduced glucose transport activity. IL-15 immunoreactivity and mRNA level in gastrocnemius muscle were decreased markedly as compared with controls. IL-15Rα protein and mRNA levels in both soleus and gastrocnemius muscle were significantly decreased, which might attenuate the signaling or secretion of IL-15 in muscle. Eight-week treadmill running completely ameliorated HFD-induced IR and reversed the downregulated level of IL-15 and IL-15Rα in skeletal muscle of HFD-fed rats. To investigate whether IL-15 exerts its anti-IR effects directly in muscle, we pre-incubated muscle strips with the endoplasmic reticulum stress (ERS) inducer dithiothreitol (DTT) or tunicamycin (Tm); IL-15 treatment markedly decreased the protein expression of the ERS markers 78-kDa glucose-regulated protein, 94-kDa glucose-regulated protein and C/EBP homologous protein and inhibited ERS induced by DTT or Tm. Therefore, treadmill running promoted skeletal IL-15 and IL-15Rα expression in HFD-induced IR in rats. The inhibitory effect of IL-15 on ERS may be involved in improved insulin sensitivity with exercise training.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. M. Peppa, C. Koliaki, P. Nikolopoulos, S.A. Raptis, Skeletal muscle insulin resistance in endocrine disease. J. Biomed. Biotechnol. 2010, 527850 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  2. M.C. Venables, A.E. Jeukendrup, Physical inactivity and obesity: links with insulin resistance and type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 5(Suppl 1), S18–S23 (2009)

    Article  Google Scholar 

  3. M.A. Febbraio, N. Hiscock, M. Sacchetti, C.P. Fischer, B.K. Pedersen, Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648 (2004)

    Article  CAS  PubMed  Google Scholar 

  4. N.B. Ruderman, C. Keller, A.M. Richard, A.K. Saha, Z. Luo, X. Xiang, M. Giralt, V.B. Ritov, E.V. Menshikova, D.E. Kelley et al., Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55, S48–S54 (2006)

    Article  CAS  PubMed  Google Scholar 

  5. B.K. Pedersen, M. Pedersen, K.S. Krabbe, H. Bruunsgaard, V.B. Matthews, M.A. Febbraio, Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp. Physiol. 94, 1153–1160 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. K.S. Krabbe, A.R. Nielsen, R. Krogh-Madsen, P. Plomgaard, P. Rasmussen, C. Erikstrup, D. Vyagova, V.N. Peneva, L. Aloe, Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50, 431–438 (2007)

    Article  CAS  PubMed  Google Scholar 

  7. J.M. Argilés, M. Orpí, S. Busquets, F.J. López-Soriano, Myostatin: more than just a regulator of muscle mass. Drug Discov. Today 17, 702–709 (2012)

    Article  PubMed  Google Scholar 

  8. A. Di Sabatino, S.A. Calarota, F. Vidali, T.T. Macdonald, G.R. Corazza, Role of IL-15 in immune-mediated and infectious diseases. Cytokine Growth Factor Rev. 22, 19–33 (2011)

    Article  PubMed  Google Scholar 

  9. L.S. Quinn, K.L. Haugk, K.H. Grabstein, Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 136, 3669–3672 (1995)

    CAS  PubMed  Google Scholar 

  10. T. Sugiura, M. Harigai, Y. Kawaguchi, K. Takagi, C. Fukasawa, S. Ohsako-Higami, S. Ohta, M. Tanaka, M. Hara, N. Kamatani, Increased IL-15 production of muscle cells in polymyositis and dermatomyositis. Int. Immunol. 14, 917–924 (2002)

    Article  CAS  PubMed  Google Scholar 

  11. L.S. Quinn, B.G. Anderson, R.H. Drivdahl, B. Alvarez, J.M. Argilés, Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders. Exp. Cell Res. 280, 55–63 (2002)

    Article  CAS  PubMed  Google Scholar 

  12. N. Carbó, J. López-Soriano, P. Costelli, S. Busquets, B. Alvarez, F.M. Baccino, L.S. Quinn, F.J. López-Soriano, J.M. Argilés, Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Br. J. Cancer 83, 526–531 (2000)

    Article  PubMed Central  PubMed  Google Scholar 

  13. G. Fuster, V. Almendro, C.C. Fontes-Oliveira, M. Toledo, P. Costelli, S. Busquets, F.J. López-Soriano, J.M. Argilés, Interleukin-15 affects differentiation and apoptosis in adipocytes: implications in obesity. Lipids 46, 1033–1042 (2011)

    Article  CAS  PubMed  Google Scholar 

  14. N.G. Barra, S. Reid, R. MacKenzie, G. Werstuck, B.L. Trigatti, C. Richards, A.C. Holloway, A.A. Ashkar, Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity (Silver Spring) 18, 1601–1607 (2010)

    Article  CAS  Google Scholar 

  15. N.G. Barra, M.V. Chew, A.C. Holloway, A.A. Ashkar, Interleukin-15 treatment improves glucose homeostasis and insulin sensitivity in obese mice. Diabetes Obes. Metab. 14, 190–193 (2012)

    Article  CAS  PubMed  Google Scholar 

  16. L.S. Quinn, B.G. Anderson, J.D. Conner, E.E. Pistilli, T. Wolden-Hanson, Overexpression of interleukin-15 in mice promotes resistance to diet-induced obesity, increased insulin sensitivity, and markers of oxidative skeletal muscle metabolism. Int. J. Interferon Cytokine Mediat. Res. 3, 29–42 (2011)

    Article  CAS  Google Scholar 

  17. L.S. Quinn, B.G. Anderson, L. Strait-Bodey, A.M. Stroud, J.M. Argilés, Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am. J. Physiol. Endocrinol. Metab. 296, E191–E202 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. S. Busquets, M. Figueras, V. Almendro, F.J. Lopez-Soriano, J.M. Argiles, Interleukin-15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim. Biophys. Acta 1760, 1613–1617 (2006)

    Article  CAS  PubMed  Google Scholar 

  19. S.R. Gray, T. Kamolrat, The effect of exercise induced cytokines on insulin stimulated glucose transport in C2C12 cells. Cytokine 55, 221–228 (2011)

    Article  CAS  PubMed  Google Scholar 

  20. A.R. Nielsen, P. Hojman, C. Erikstrup, C.P. Fischer, P. Plomgaard, R. Mounier, O.H. Mortensen, C. Broholm, S. Taudorf, R. Krogh-Madsen et al., Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J. Clin. Endocrinol. Metab. 93, 4486–4493 (2008)

    Article  CAS  PubMed  Google Scholar 

  21. A. Rinnov, C. Yfanti, S. Nielsen, T.C. Akerström, L. Peijs, A. Zankari, C.P. Fischer, B.K. Pedersen, Endurance training enhances skeletal muscle interleukin-15 in human male subjects. Endocrine 45, 271–278 (2014)

    Article  CAS  PubMed  Google Scholar 

  22. P. Boström, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach, E.A. Boström, J.H. Choi, J.Z. Long et al., A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  23. N.H. Yeo, J. Woo, K.O. Shin, J.Y. Park, S. Kang, The effects of different exercise intensity on myokine and angiogenesis factors. J. Sports Med. Phys. Fit. 52, 48–54 (2012)

    Google Scholar 

  24. M. Wagner, D.D. Moore, Endoplasmic reticulum stress and glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 14, 367–373 (2011)

    Article  CAS  PubMed  Google Scholar 

  25. S. Sundar Rajan, V. Srinivasan, M. Balasubramanyam, U. Tatu, Endoplasmic reticulum (ER) stress and diabetes. Indian J. Med. Res. 125, 411–424 (2007)

    CAS  PubMed  Google Scholar 

  26. L. Deldicque, P. Hespel, M. Francaux, Endoplasmic reticulum stress in skeletal muscle: origin and metabolic consequences. Exerc. Sport Sci. Rev. 40, 43–49 (2012)

    Article  PubMed  Google Scholar 

  27. S.L. Hwang, H.W. Chang, I.K. Lee, B.K. Yang, J. Magae, Y.C. Chang, Ascofuranone prevents ER stress-induced insulin resistance via activation of AMP-activated protein kinase in L6 myotube cells. Biochem. Biophys. Res. Commun. 396, 967–972 (2010)

    Article  CAS  PubMed  Google Scholar 

  28. G.A. Raciti, C. Iadicicco, L. Ulianich, B.F. Vind, M. Gaster, F. Andreozzi, M. Longo, R. Teperino, P. Ungaro, B. Di Jeso et al., Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 53, 955–965 (2010)

    Article  CAS  PubMed  Google Scholar 

  29. E.K. Yoon, Y.T. Jeong, X. Li, Song-Cui, D.C. Park, Y.H. Kim, Y.D. Kim, H.W. Chang, S.H. Lee, S.L. Hwang, Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK–AMPK pathway in L6 myotubes. J. Nutr. Biochem. 24, 1053–1061 (2013)

    Article  CAS  PubMed  Google Scholar 

  30. S.L. Hwang, Y.T. Jeong, X. Li, Y.D. Kim, Y. Lu, Y.C. Chang, I.K. Lee, H.W. Chang, Inhibitory cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Br. J. Pharmacol. 169, 69–81 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. K.S. Gollisch, J. Brandauer, N. Jessen, T. Toyoda, A. Nayer, M.F. Hirshman, L.J. Goodyear, Am. J. Physiol. Endocrinol. Metab. 297, E495–E504 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. M.S. Gauthier, K. Couturier, A. Charbonneau, J.M. Lavoie, Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile. Int. J. Obes. Relat. Metab. Disord. 28, 1064–1071 (2004)

    Article  PubMed  Google Scholar 

  33. D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985)

    Article  CAS  PubMed  Google Scholar 

  34. M.C. Blendea, D. Jacobs, C.S. Stump, S.I. McFarlane, C. Ogrin, G. Bahtyiar, S. Stas, P. Kumar, Q. Sha, C.M. Ferrario et al., Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression. Am. J. Physiol. Endocrinol. Metab. 288, E353–E359 (2005)

    Article  CAS  PubMed  Google Scholar 

  35. E.E. Pistilli, J.M. Devaney, H. Gordish-Dressman, M.K. Bradbury, R.L. Seip, P.D. Thompson, T.J. Angelopoulos, P.M. Clarkson, N.M. Moyna, L.S. Pescatello et al., Interleukin-15 and interleukin-15R alpha SNPs and associations with muscle, bone, and predictors of the metabolic syndrome. Cytokine 43, 45–53 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. A.R. Nielsen, P. Hojman, C. Erikstrup, C.P. Fischer, P. Plomgaard, R. Mounier, O.H. Mortensen, C. Broholm, S. Taudorf, R. Krogh-Madsen et al., Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J. Clin. Endocrinol. Metab. 93, 4486–4493 (2008)

    Article  CAS  PubMed  Google Scholar 

  37. H.J. Kim, J.Y. Park, S.L. Oh, Y.A. Kim, B. So, J.K. Seong, W. Song, Effect of treadmill exercise on interleukin-15 expression and glucose tolerance in zucker diabetic fatty rats. Diabetes Metab. J. 37, 358–364 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  38. M. Molanouri Shamsi, Z.H. Hassan, R. Gharakhanlou, L.S. Quinn, K. Azadmanesh, L. Baghersad, A. Isanejad, M. Mahdavi, Expression of interleukin-15 and inflammatory cytokines in skeletal muscles of STZ-induced diabetic rats: effect of resistance exercise training. Endocrine (2013). doi:10.1007/s12020-013-0038-4

    PubMed  Google Scholar 

  39. A.R. Nielsen, R. Mounier, P. Plomgaard, O.H. Mortensen, M. Penkowa, T. Speerschneider, H. Pilegaard, B.K. Pedersen, Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J. Physiol. 584, 305–312 (2007)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. E.E. Pistilli, L.S. Quinn, From anabolic to oxidative: reconsidering the roles of IL-15 and IL-15Rα in skeletal muscle. Exerc. Sport Sci. Rev. 41, 100–106 (2013)

    Article  PubMed  Google Scholar 

  41. L. Deldicque, P.D. Cani, A. Philp, J.M. Raymackers, P.J. Meakin, M.L. Ashford, N.M. Delzenne, M. Francaux, K. Baar, The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the down-regulation of protein synthesis. Am. J. Physiol. Endocrinol. Metab. 299, E695–E705 (2010)

    Article  CAS  PubMed  Google Scholar 

  42. M. Boyce, J. Yuan, Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 13, 363–373 (2006)

    Article  CAS  PubMed  Google Scholar 

  43. G. Peng, L. Li, Y. Liu, J. Pu, S. Zhang, J. Yu, J. Zhao, P. Liu, Oleate blocks palmitate-induced abnormal lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal muscle. Endocrinology 152, 2206–2218 (2011)

    Article  CAS  PubMed  Google Scholar 

  44. U. Ozcan, E. Yilmaz, L. Ozcan, M. Furuhashi, E. Vaillancourt, R.O. Smith, C.Z. Görgün, G.S. Hotamisligil, Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006)

    Article  PubMed  Google Scholar 

  45. S.W. Park, U. Ozcan, Potential for therapeutic manipulation of the UPR in disease. Semin Immunopathol. 35, 351–373 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. G. da Luz, M.J. Frederico, S. da Silva, M.F. Vitto, P.A. Cesconetto, R.A. de Pinho, J.R. Pauli, A.S. Silva, D.E. Cintra, E.R. Ropelle et al., Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. Eur. J. Appl. Physiol. 111, 2015–2023 (2011)

    Article  PubMed  Google Scholar 

  47. J. Wu, J.L. Ruas, J.L. Estall, K.A. Rasbach, J.H. Choi, L. Ye, P. Boström, H.M. Tyra, R.W. Crawford, K.P. Campbell et al., The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1alpha/ATF6alpha complex. Cell Metab. 13, 160Y9 (2011)

    Article  Google Scholar 

  48. C.C. Glembotski, Endoplasmic reticulum stress in the heart. Circ. Res. 101, 975–984 (2007)

    Article  CAS  PubMed  Google Scholar 

  49. G. Fuster, S. Busquets, M. Figueras, E. Ametller, C.C. Fontes de Oliveira, M. Oliván, P.A. Grimaldi, J.M. Argilés, F.J. López-Soriano, PPARdelta mediates IL15 metabolic actions in myotubes: effects of hyperthermia. Int. J. Mol. Med. 24, 63–68 (2009)

    CAS  PubMed  Google Scholar 

  50. L.S. Quinn, B.G. Anderson, J.D. Conner, T. Wolden-Hanson, IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARδ, SIRT1, PGC-1α, and PGC-1β expression in male mice. Endocrinology 154, 232–245 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. L.S. Quinn, B.G. Anderson, J.D. Conner, T. Wolden-Hanson, T.J. Marcell, IL-15 is required for postexercise induction of the pro-oxidative mediators PPARδ and SIRT1 in male mice. Endocrinology 155, 143–155 (2014)

    Article  PubMed  Google Scholar 

  52. M. Cao, Y. Tong, Q. Lv, X. Chen, Y. Long, L. Jiang, J. Wan, Y. Zhang, F. Zhang, N. Tong, PPARδ activation rescues pancreatic β-cell line INS-1E from palmitate-induced endoplasmic reticulum stress through enhanced fatty acid oxidation. PPAR Res. 2012, 680684 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  53. T. Ramirez, M. Tong, W.C. Chen, Q.G. Nguyen, J.R. Wands, S.M. de la Monte, Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment. J. Gastroenterol. Hepatol. 28, 179–187 (2013)

    Article  CAS  PubMed  Google Scholar 

  54. T.W. Jung, K.T. Lee, M.W. Lee, K.H. Ka, SIRT1 attenuates palmitate-induced endoplasmic reticulum stress and insulin resistance in HepG2 cells via induction of oxygen-regulated protein 150. Biochem. Biophys. Res. Commun. 422, 229–232 (2012)

    Article  CAS  PubMed  Google Scholar 

  55. Y. Li, S. Xu, A. Giles, K. Nakamura, J.W. Lee, X. Hou, G. Donmez, J. Li, Z. Luo, K. Walsh, Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 25, 1664–1679 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant nos. 81270921 and 81170082).

Ethical standards

All animal care and experimental protocols complied with the Animal Management Rules (document No. 55, 2001) of the Ministry of Health of the People’s Republic of China and the guide for the Care and Use of the Laboratory Animals of Peking University Health Science Center.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. School of P.E. and Sports Science, Beijing Normal University, Beijing, 100875, China

    Hong-Tao Yang & Jing Zhang

  2. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China

    Lei Zhao, Chao-Shu Tang & Yong-Fen Qi

  3. Qufu Normal University, Shandong, 273165, China

    Li-Jie Luo

  4. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China

    Wen-Jia Chen

Authors
  1. Hong-Tao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-Jie Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Jia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao-Shu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong-Fen Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, HT., Luo, LJ., Chen, WJ. et al. IL-15 expression increased in response to treadmill running and inhibited endoplasmic reticulum stress in skeletal muscle in rats. Endocrine 48, 152–163 (2015). https://doi.org/10.1007/s12020-014-0233-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0233-y

Keywords

Search

Navigation