Skip to main content

Advertisement

SpringerLink
Log in

Expression of interleukin-15 and inflammatory cytokines in skeletal muscles of STZ-induced diabetic rats: effect of resistance exercise training

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

Abstract

Skeletal muscle atrophy is associated with type-1 diabetes. Skeletal muscle is the source of pro- and anti-inflammatory cytokines that can mediate muscle hypertrophy and atrophy, while resistance exercise can modulate both muscle mass and muscle cytokine expression. This study determined the effects of a 5-week resistance exercise training regimen on the expression of muscle cytokines in healthy and streptozotocin-induced diabetic rats, with special emphasis on interleukin-15 (IL-15), a muscle-derived cytokine proposed to be involved in muscle hypertrophy or responses to stress. Induction of diabetes reduced muscle weight in both the fast flexor hallucis longus (FHL) and slow soleus muscles, while resistance training preserved FHL muscle weight in diabetic rats. IL-15 protein content was increased by training in both FHL and soleus muscles, as well as serum, in normal and diabetic rats. With regard to proinflammatory cytokines, muscle IL-6 levels were increased in diabetic rats, while training decreased muscle IL-6 levels in diabetic rats; training had no effect on FHL muscle IL-6 levels in healthy rats. Also, tumor necrosis factor-alpha (TNF-α) and IL-1β levels were increased by diabetes, but not changed by training. In conclusion, we found that in diabetic rats, resistance training increased muscle and serum IL-15 levels, decreased muscle IL-6 levels, and preserved FHL muscle mass.

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

Similar content being viewed by others

References

  1. B.C. Frier, E.G. Noble, M. Locke, Diabetes-induced atrophy is associated with a muscle-specific alteration in NF-kappaB activation and expression. Cell Stress Chaperones 13(3), 287–296 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. H. Andersen, P.C. Gadeberg, B. Brock, J. Jakobsen, Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study. Diabetologia 40(9), 1062–1069 (1997)

    Article  CAS  PubMed  Google Scholar 

  3. R.A. Frost, C.H. Lang, Regulation of muscle growth by pathogen-associated molecules. J. Anim. Sci. 86(14), 84–93 (2008)

    Article  Google Scholar 

  4. G.Q. Chen, C.Y. Mou, Y.Q. Yang, S. Wang, Z.W. Zhao, Exercise training has beneficial anti-atrophy effects by inhibiting oxidative stress-induced MuRF1 upregulation in rats with diabetes. Life Sci. 89(1–2), 44–49 (2011)

    Article  CAS  PubMed  Google Scholar 

  5. R.B. Hunter, E. Stevenson, A. Koncarevic, H. Mitchell-Felton, D.A. Essig, S.C. Kandarian, Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. FASEB J 16(6), 529–538 (2002)

    Article  CAS  PubMed  Google Scholar 

  6. L.G. Karagounis, B.B. Yaspelkis 3rd, D.W. Reeder, G.I. Lancaster, J.A. Hawley, V.G. Coffey, Contraction-induced changes in TNF alpha and Akt mediated signalling are associated with increased myofibrillar protein in rat skeletal muscle. Eur. J. Appl. Physiol. 109(5), 48–839 (2010)

    Article  Google Scholar 

  7. L.S. Quinn, B.G. Anderson, R.H. Drivdahl, B. Alvarez, J.M. Argilés, Overexpression of interleukin15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders. Exp. Cell Res. 280(1), 55–63 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. F.S. Lira, C.H. Koyama, A.S. Yamashita, J.C. Rosa, N.E. Zanchi, M.L. Batista Jr et al., Chronic exercise decreases cytokines production in healthy rat skeletal muscle. Cell Biochem. Funct. 27, 458–461 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. N.E. Zanchi, F.S. Lira, M.A. de Siqueira Filho, J.C. Rosa, C.R. de Oliveira Carvalho, M. Seelaender et al., Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle. Eur. J. Appl. Physiol. 109(6), 1095–1102 (2010)

    Article  CAS  PubMed  Google Scholar 

  10. S.C. Forbes, J.P. Little, D.G. Candow, Exercise and nutritional interventions for improving aging muscle health. Endocrine 42(1), 29–38 (2012)

    Article  CAS  PubMed  Google Scholar 

  11. B.K. Pedersen, M.A. Febbraio, Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88(4), 1379–1406 (2008)

    Article  CAS  PubMed  Google Scholar 

  12. F. Haddad, G.R. Adams, Selected contribution: acute cellular and molecular responses to resistance exercise. J. Appl. Physiol. 93, 394–403 (2002)

    CAS  PubMed  Google Scholar 

  13. T.O. Takala, P. Nuutila, J. Knuuti, M. Luotolahti, H. Yki-Järvinen, Insulin action on heart and skeletal muscle glucose uptake in weight lifters and endurance athletes. Am. J. Physiol. 276(4 Pt 1), E706–E711 (1999)

    CAS  PubMed  Google Scholar 

  14. J.O. Holloszy, Exercise-induced increase in muscle insulin sensitivity. J. Appl. Physiol. 99(1), 338–343 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. A.L. Carey, G.R. Steinberg, S.L. Macaulay, W.G. Thomas, A.G. Holmes, G. Ramm et al., Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acidoxidation in vitro via AMP-activated protein kinase. Diabetes 55(10), 2688–2697 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. K.H. Grabstein, J. Eisenman, K. Shanebeck, C. Rauch, S. Srinivasan, V. Fung et al., Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 264(5161), 965–968 (1994)

    Article  CAS  PubMed  Google Scholar 

  17. H.C. Kim, H.Y. Cho, Y.S. Hah, Role of IL-15 in sepsis-induced skeletal muscle atrophy and proteolysis. Tuberc. Respir. Dis. (Seoul) 73(6), 312–319 (2012)

    Article  CAS  PubMed Central  Google Scholar 

  18. M. Figueras, S. Busquets, N. Carbó, E. Barreiro, V. Almendro, J.M. Argilés et al., Interleukin 15 is able to suppress the increased DNA fragmentation associated with musclewasting in tumour-bearing rats. FEBS Lett 569(1–3), 201–206 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. J. Xia, W. Liu, B. Hu, Z. Tian, Y. Yang, IL-15promotes regulatory T cell function and protects against diabetes development in NK-depleted NOD mice. Clin Immunol 134(2), 130–139 (2010)

    Article  CAS  PubMed  Google Scholar 

  20. S. Kuczyński, H. Winiarska, M. Abramczyk, K. Szczawińska, B. Wierusz-Wysocka, M. Dworacka, IL-15 is elevated in serum patients with type 1 diabetes mellitus. Diabetes Res. Clin. Pract. 69(3), 231–236 (2005)

    Article  PubMed  Google Scholar 

  21. S.R. Gray, T. Kamolrat, The effect of exercise induced cytokines on insulin stimulated glucose transport in C2C12 cells. Cytokine 55(2), 221–228 (2011)

    Article  CAS  PubMed  Google Scholar 

  22. S.E. Riechman, G. Balasekaran, S.M. Roth, R.E. Ferrell, Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses. J. Appl. Physiol. 97, 2214–2219 (2004)

    Article  CAS  PubMed  Google Scholar 

  23. A.R. Nielsen, R. Mounier, P. Plomgaard, O.H. Mortensen, M. Penkowa, T. Speerschneider et al., Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J. Physiol. 584(Pt 1), 305–312 (2007)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. L.S. Quinn, B.G. Anderson, L. Strait-Bodey, T. Wolden-Hanson, Serum and muscle interleukin-15 levels decrease in aging mice: correlation with declines in soluble interleukin-15 receptor alpha expression. Exp. Gerontol. 45(2), 106–112 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. E. Marzetti, C.S. Carter, S.E. Wohlgemuth, H.A. Lees, S. Giovannini, B. Anderson et al., Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mech. Ageing Dev. 130(4), 272–280 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. E.E. Pistilli, P.M. Siu, S.E. Alway, Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy. Am. J. Physiol. Cell Physiol. 292(4), C1298–C1304 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Y. Tamura, K. Watanabe, T. Kantani, J. Hyashi, N. Ishida, M. Kaneki, Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr. J. 58, 211–215 (2011)

    Article  CAS  PubMed  Google Scholar 

  28. S. Lee, E.R. Barton, H.L. Sweeney, R.P. Farrar, Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats. J. Appl. Physiol. 96(3), 1097–1104 (2004)

    Article  CAS  PubMed  Google Scholar 

  29. P.A. Farrell, M.J. Fedele, J. Hernandez, J.D. Fluckey, J.L. Miller 3rd, C.H. Lang et al., Hypertrophy of skeletal muscle in diabetic rats in response to chronic resistance exercise. J. Appl. Physiol. 87(3), 1075–1082 (1999)

    CAS  PubMed  Google Scholar 

  30. E. Talebi-Garakani, A. Safarzade, Resistance training decreases serum inflammatory markers in diabetic rats. Endocrine 43(3), 564–570 (2013)

    Article  CAS  PubMed  Google Scholar 

  31. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4), 402–408 (2001)

    Article  CAS  PubMed  Google Scholar 

  32. M.M. Bradford, A rapid and sensitive method for quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976)

    Article  CAS  PubMed  Google Scholar 

  33. T.A. Hornberger Jr, R.P. Farrar, Physiological hypertrophy of the FHL muscle following 8 weeks of progressive resistance exercise in the rat. Can. J. Appl. Physiol. 29(1), 16–31 (2004)

    Article  CAS  PubMed  Google Scholar 

  34. H. Yang, J. Chang, W. Chen, L. Zhao, B. Qu, C. Tang et al., Treadmill exercise promotes interleukin 15 expression in skeletal muscle and interleukin 15 receptor alphaexpression in adipose tissue of high-fat diet rats. Endocrine 43(3), 579–585 (2013)

    Article  CAS  PubMed  Google Scholar 

  35. T.A. Fehniger, M.A. Caligiuri, Interleukin 15: biology and relevance to human disease. Blood 97, 14–32 (2001)

    Article  CAS  PubMed  Google Scholar 

  36. V. Budagian, E. Bulanova, R. Paus, S. Bulfone-Paus, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev. 17(4), 259–280 (2006)

    Article  CAS  PubMed  Google Scholar 

  37. K. Baar, K. Esser, Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am. J. Physiol. 276(1 Pt 1), C120–C127 (1999)

    CAS  PubMed  Google Scholar 

  38. M. Cesari, B.W. Penninx, M. Pahor, F. Lauretani, A.M. Corsi, W.G. Rhys et al., Inflammatory markers and physical performance in older persons: the In CHIANTI study. J. Gerontol. A Biol. Sci. Med. Sci. 59, 242–248 (2004)

    Article  PubMed  Google Scholar 

  39. L.H. Colbert, M. Visser, E.M. Simonsick, R.P. Tracy, A.B. Newman, S.B. Kritchevsky et al., Physical activity, exercise, inflammatory markers in older adults: findings from the health, aging and body composition study. J. Am. Geriatr. Soc. 52, 1098–1104 (2004)

    Article  PubMed  Google Scholar 

  40. 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. Sport. Med. Phys. Fit. 52(4), 448–454 (2012)

    CAS  Google Scholar 

  41. M. Gleeson, Interleukins and exercise. J. Physiol. 529(Pt 1), 1 (2000)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. N.B. Abdulrazaq, M.M. Cho, N.N. Win, R. Zaman, M.T. Rahman, Beneficial effects of ginger (Zingiber officinale) on carbohydrate metabolism in streptozotocin-induced diabetic rats. Br. J. Nutr. 12, 1–8 (2011)

    Google Scholar 

  43. O. Bozkurt, M. Severcan, F. Severcan, Diabetes induces compositional, structural and functional alterations on rat skeletal soleus muscle revealed by FTIR spectroscopy: a comparative study with EDL muscle. Analyst 135(12), 3110–3119 (2010)

    Article  CAS  PubMed  Google Scholar 

  44. J.F. Liu, W.Y. Chang, K.H. Chan, W.Y. Tsai, C.L. Lin, M.C. Hsu, Blood lipid peroxides and muscle damage increased following intensive resistance training of female weightlifters. Ann. N. Y. Acad. Sci. 1042, 255–261 (2005)

    Article  CAS  PubMed  Google Scholar 

  45. C. Scheele, S. Nielsen, B.K. Pedersen, ROS and myokines promote muscle adaptation to exercise. Trends Endocrinol. Metab. 20(3), 95–99 (2009)

    Article  CAS  PubMed  Google Scholar 

  46. S. Copray, R. Liem, N. Brouwer, P. Greenhaff, F. Habens, P. Fernyhough, Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associateed with elevated expression of brain derived neurotrophic factor mRNA in muscle fibers and activated satellite cells. Exp. Neurol. 161(2), 597–608 (2000)

    Article  CAS  PubMed  Google Scholar 

  47. A. Rabinovitch, W.L. Suarez-Pinzon, Cytokines and their roles in pancreatic islet h-cell destruction and insulin-dependent diabetes mellitus. Biochem. Pharmacol. 55, 1139–1149 (1998)

    Article  CAS  PubMed  Google Scholar 

  48. S.K. Jain, K. Kannan, G. Lim, R. McVie, J.A. Bocchini, Hyperketonemia increases TNF-α secretion in cultured U937 monocytes and type-1 diabetic patients. Diabetes 51, 2287–2293 (2002)

    Article  CAS  PubMed  Google Scholar 

  49. M.G. Cavallo, P. Pozzilli, C. Bird, M. Wadhwa, A. Meager, N. Visalli et al., Cytokines in sera from insulin dependent diabetic patients at diagnosis. Clin. Exp. Immunol. 86, 256–259 (1991)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. R.A. Frost, G.J. Nystrom, C.H. Lang, Lipopolysaccharide and proinflammatory cytokines stimulate interleukin-6 expression in C2C12 myoblasts: role of the Jun NH2-terminal kinase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R1153–R1164 (2003)

    CAS  PubMed  Google Scholar 

  51. H. Klitgaard, A model for quantitative strength training of hindlimb muscles of the rat. J. Appl. Physiol. 64(4), 1740–1745 (1988)

    CAS  PubMed  Google Scholar 

  52. G. Whyte, The Physiology of Training (Advances in Sport and Exercise Science) (Amazon, 2006), pp. 135–161

  53. R.S. Staron, R.S. Hikida, T.F. Murray, M.M. Nelson, P. Johnson, F.C. Hagerman, Assessment of skeletal muscle damage in successive biopsies from strength-trained and untrained men and women. Eur. J. Appl. Physiol. 65, 258–264 (1992)

    Article  CAS  Google Scholar 

  54. S.M. Roth, G.F. Martel, F.M. Ivey, J.T. Lemmer, E.J. Metter, B.F. Hurley, M.A. Rogers, High-volume, heavy-resistance strength training and muscle damage in young and older women. J. Appl. Physiol. 88(3), 1112–1118 (2000)

    CAS  PubMed  Google Scholar 

  55. N.E. Zanchi, F.S. Lira, M. Seelaender, A.H. Lancha-Jr, Experimental chronic low-frequency resistance training produces skeletal muscle hypertrophy in the absence of muscle damage and metabolic stress markers. Cell Biochem. Funct. 28(3), 232–238 (2010)

    Article  CAS  PubMed  Google Scholar 

  56. D. Hansen, B.O. Eijnde, M. Roelants, T. Broekmans, J.L. Rummens, K. Hensen et al., Clinical benefits of the addition of lower extremity low-intensity resistance muscle training to early aerobic endurance training intervention in patients with coronary artery disease: a randomized controlled trial. J. Rehabil. Med. 43(9), 800–807 (2011)

    Article  PubMed  Google Scholar 

  57. S.L. Lee, K.W. Chen, S.T. Chen, P.J. Chu, C.S. Chen, M.C. Hsu et al., Effect of passive repetitive isokinetic training on cytokines and hormonal changes. Chin. J. Physiol. 54(1), 55–66 (2011)

    Article  CAS  PubMed  Google Scholar 

  58. A.L. Mackey, M. Kjaer, S. Dandanell, K.H. Mikkelsen, L. Holm, S. Dossing et al., The influence of anti-inflammatory medication on exercise-induced myogenic precursor cell responses in humans. J. Appl. Physiol. 103, 425–431 (2007)

    Article  CAS  PubMed  Google Scholar 

  59. Q.A. Soltow, J.L. Betters, J.E. Sellman, V.A. Lira, J.H. Long, D.S. Criswell, Ibuprofen inhibits skeletal muscle hypertrophy in rats. Med. Sci. Sport. Exerc. 38, 840–846 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Research Center of Tarbiat Modares University (TMU), Tehran, Iran. We wish to thank Professor Yaghob Fathoallahy and Dr Alireza Mani for their kind help and sincere cooperation.

Conflict of interest

The authors of this research article have no financial and personal conflict of interest statement.

Author information

Authors and Affiliations

  1. Physical Education & Sport Sciences Department, Faculty of Humanities, Tarbiat Modares University, Jala Ale Ahmad Exp, 14117-13116, Tehran, Islamic Republic of Iran

    M. Molanouri Shamsi, R. Gharakhanlou & L. Baghersad

  2. Department of Immunology, School of Medical Sciences, Tarbiat Modares University, Jala Ale Ahmad Exp, 14115-13116, Tehran, Islamic Republic of Iran

    Z. H. Hassan

  3. Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98108, USA

    L. S. Quinn

  4. Virology Department, Pasteur Institute of Iran, 69 Pasteur Ave, Tehran, Islamic Republic of Iran

    K. Azadmanesh & M. Mahdavi

  5. Physical Education & Sport Sciences Department, Faculty of Humanities, Shahed University, Tehran, Islamic Republic of Iran

    A. Isanejad

Authors
  1. M. Molanouri Shamsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z. H. Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Gharakhanlou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. S. Quinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Azadmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Baghersad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Isanejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Mahdavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M. Molanouri Shamsi or M. Mahdavi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molanouri Shamsi, M., Hassan, Z.H., Gharakhanlou, R. et al. Expression of interleukin-15 and inflammatory cytokines in skeletal muscles of STZ-induced diabetic rats: effect of resistance exercise training. Endocrine 46, 60–69 (2014). https://doi.org/10.1007/s12020-013-0038-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-013-0038-4

Keywords

Search

Navigation