Skip to main content

Advertisement

Log in

Role of irisin in effects of chronic exercise on muscle and bone in ovariectomized mice

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

Exercise is beneficial for the prevention and treatment of osteoporosis. Skeletal muscle affects other tissues via myokines, the release of which is regulated by acute exercise. However, the effects of chronic exercise on myokines linking muscle to bone have not been fully elucidated. Therefore, we investigated the effects of chronic exercise on bone and myokines using ovariectomized (OVX) mice.

Materials and methods

Treadmill exercise with moderate intensity was performed for 8 weeks after OVX or sham surgery. We measured bone mineral density (BMD) at the femurs and tibias of mice by quantitative computed tomography and myokine mRNA levels in the gastrocnemius and soleus muscles.

Results

Treadmill exercise ameliorated decreases in trabecular and cortical BMD in the femurs of OVX mice. Irisin is a proteolytic product of fibronectin type III domain-containing 5 (Fndc5). Among the myokines examined, treadmill exercise increased irisin protein and Fndc5 mRNA levels in the gastrocnemius and soleus muscles of sham and OVX mice. Treadmill exercise increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA levels in the gastrocnemius muscles of mice. Fndc5 mRNA levels in the gastrocnemius muscles positively correlated with trabecular BMD, but not with cortical BMD, at the femurs and tibias of mice in simple regression analyses.

Conclusions

We demonstrated that chronic exercise elevated irisin expression in the gastrocnemius and soleus muscles of estrogen-deficient mice. Irisin might be related to increases in trabecular BMD in mice; however, further studies are needed to clarify the involvement of irisin in the effects of chronic exercise on muscle/bone interactions.

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

Access this article

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
Fig. 6

Similar content being viewed by others

References

  1. Smith JK (2018) Exercise, obesity and CNS control of metabolic homeostasis: a review. Front Physiol 9:574

    PubMed  PubMed Central  Google Scholar 

  2. Wallace BA, Cumming RG (2000) Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. Calcif Tissue Int 67:10–18

    CAS  PubMed  Google Scholar 

  3. Shojaa M, Von Stengel S, Schoene D, Kohl M, Barone G, Bragonzoni L, Dallolio L, Marini S, Murphy MH, Stephenson A, Manty M, Julin M, Risto T, Kemmler W (2020) Effect of exercise training on bone mineral density in post-menopausal women: A systematic review and meta-analysis of intervention studies. Front Physiol 11:652

    PubMed  PubMed Central  Google Scholar 

  4. Kemmler W, Shojaa M, Kohl M, von Stengel S (2020) Effects of different types of exercise on bone mineral density in postmenopausal women: a systematic review and meta-analysis. Calcif Tissue Int 107:409–439

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hamilton CJ, Swan VJ, Jamal SA (2010) The effects of exercise and physical activity participation on bone mass and geometry in postmenopausal women: a systematic review of pQCT studies. Osteoporos Int 21:11–23

    CAS  PubMed  Google Scholar 

  6. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192

    CAS  PubMed  Google Scholar 

  7. Duncan RL, Turner CH (1995) Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int 57:344–358

    CAS  PubMed  Google Scholar 

  8. Wang L, You X, Lotinun S, Zhang L, Wu N, Zou W (2020) Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat Commun 11:282

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gilchrist CL, Leddy HA, Kaye L, Case ND, Rothenberg KE, Little D, Liedtke W, Hoffman BD, Guilak F (2019) TRPV4-mediated calcium signaling in mesenchymal stem cells regulates aligned collagen matrix formation and vinculin tension. Proc Natl Acad Sci U S A 116:1992–1997

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, DeSimone D, Bonewald LF, Lafer EM, Sprague E, Schwartz MA, Jiang JX (2012) Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci U S A 109:3359–3364

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawao N, Kaji H (2015) Interactions between muscle tissues and bone metabolism. J Cell Biochem 116:687–695

    CAS  PubMed  Google Scholar 

  12. Kawao N, Morita H, Iemura S, Ishida M, Kaji H (2020) Roles of Dkk2 in the linkage from muscle to bone during mechanical unloading in mice. Int J Mol Sci 21:2547

    CAS  PubMed Central  Google Scholar 

  13. Shimoide T, Kawao N, Morita H, Ishida M, Takafuji Y, Kaji H (2020) Roles of olfactomedin 1 in muscle and bone alterations induced by gravity change in mice. Calcif Tissue Int 107:180–190

    CAS  PubMed  Google Scholar 

  14. Kawao N, Morita H, Obata K, Tatsumi K, Kaji H (2018) Role of follistatin in muscle and bone alterations induced by gravity change in mice. J Cell Physiol 233:1191–1201

    CAS  PubMed  Google Scholar 

  15. Kirk B, Feehan J, Lombardi G, Duque G (2020) Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep 18:388–400

    PubMed  Google Scholar 

  16. Herrmann M, Engelke K, Ebert R, Muller-Deubert S, Rudert M, Ziouti F, Jundt F, Felsenberg D, Jakob F (2020) Interactions between muscle and bone-where physics meets biology. Biomolecules 10:432

    CAS  PubMed Central  Google Scholar 

  17. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468

    PubMed  PubMed Central  Google Scholar 

  18. Perakakis N, Triantafyllou GA, Fernandez-Real JM, Huh JY, Park KH, Seufert J, Mantzoros CS (2017) Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 13:324–337

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gamas L, Matafome P, Seica R (2015) Irisin and myonectin regulation in the insulin resistant muscle: implications to adipose tissue: muscle crosstalk. J Diabetes Res 2015:359159

    PubMed  PubMed Central  Google Scholar 

  20. Kawao N, Moritake A, Tatsumi K, Kaji H (2018) Roles of irisin in the linkage from muscle to bone during mechanical unloading in mice. Calcif Tissue Int 103:24–34

    CAS  PubMed  Google Scholar 

  21. Qiao X, Nie Y, Ma Y, Chen Y, Cheng R, Yin W, Hu Y, Xu W, Xu L (2016) Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci Rep 6:18732

    CAS  PubMed  Google Scholar 

  22. Colaianni G, Cuscito C, Mongelli T, Oranger A, Mori G, Brunetti G, Colucci S, Cinti S, Grano M (2014) Irisin enhances osteoblast differentiation in vitro. Int J Endocrinol 2014:902186

    PubMed  PubMed Central  Google Scholar 

  23. Chen X, Sun K, Zhao S, Geng T, Fan X, Sun S, Zheng M, Jin Q (2020) Irisin promotes osteogenic differentiation of bone marrow mesenchymal stem cells by activating autophagy via the Wnt/β-catenin signal pathway. Cytokine 136:155292

    CAS  PubMed  Google Scholar 

  24. Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L, Spiro G, Notarnicola A, Severi I, Passeri G, Mori G, Brunetti G, Moretti B, Tarantino U, Colucci SC, Reseland JE, Vettor R, Cinti S, Grano M (2017) Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci Rep 7:2811

    PubMed  PubMed Central  Google Scholar 

  25. Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C et al (2015) The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A 112:12157–12162

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Iemura S, Kawao N, Okumoto K, Akagi M, Kaji H (2020) Role of irisin in androgen-deficient muscle wasting and osteopenia in mice. J Bone Miner Metab 38:161–171

    CAS  PubMed  Google Scholar 

  27. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y et al (2018) Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175(1756–1768):e1717

    Google Scholar 

  28. Shiomi A, Kawao N, Yano M, Okada K, Tamura Y, Okumoto K, Matsuo O, Akagi M, Kaji H (2015) α2-Antiplasmin is involved in bone loss induced by ovariectomy in mice. Bone 79:233–241

    CAS  PubMed  Google Scholar 

  29. Wang N, Liu Y, Ma Y, Wen D (2017) High-intensity interval versus moderate-intensity continuous training: superior metabolic benefits in diet-induced obesity mice. Life Sci 191:122–131

    CAS  PubMed  Google Scholar 

  30. Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486

    PubMed  Google Scholar 

  31. Wu J, Wang XX, Takasaki M, Ohta A, Higuchi M, Ishimi Y (2001) Cooperative effects of exercise training and genistein administration on bone mass in ovariectomized mice. J Bone Miner Res 16:1829–1836

    CAS  PubMed  Google Scholar 

  32. Sun X, Li F, Ma X, Ma J, Zhao B, Zhang Y, Li Y, Lv J, Meng X (2015) The Effects of combined treatment with naringin and treadmill exercise on osteoporosis in ovariectomized rats. Sci Rep 5:13009

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma Y, Qiao X, Zeng R, Cheng R, Zhang J, Luo Y, Nie Y, Hu Y, Yang Z, Liu L, Xu W, Xu CC, Xu L (2018) Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells. FASEB J. https://doi.org/10.1096/fj.201700983RR

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhang J, Valverde P, Zhu X, Murray D, Wu Y, Yu L, Jiang H, Dard MM, Huang J, Xu Z, Tu Q, Chen J (2017) Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism. Bone Res 5:16056

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, Nair KS, Gygi SP, Spiegelman BM (2015) Detection and quantitation of circulating human Irisin by tandem mass spectrometry. Cell Metab 22:734–740

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418:797–801

    CAS  PubMed  Google Scholar 

  37. Fuller SE, Huang TY, Simon J, Batdorf HM, Essajee NM, Scott MC, Waskom CM, Brown JM, Burke SJ, Collier JJ (1985) Noland RC (2019) Low-intensity exercise induces acute shifts in liver and skeletal muscle substrate metabolism but not chronic adaptations in tissue oxidative capacity. J Appl Physiol 127:143–156

    Google Scholar 

  38. Gaspar RC, Veiga CB, Bessi MP, Datilo MN, Sant’Ana MR, Rodrigues PB, de Moura LP, da Silva ASR, Santos GA, Catharino RR, Ropelle ER, Pauli JR, Cintra DE (2019) Unsaturated fatty acids from flaxseed oil and exercise modulate GPR120 but not GPR40 in the liver of obese mice: a new anti-inflammatory approach. J Nutr Biochem 66:52–62

    CAS  PubMed  Google Scholar 

  39. da Costa Daniele TM, de Bruin PFC, de Matos RS, de Bruin GS, Maia Chaves CJ, de Bruin VMS (2020) Exercise effects on brain and behavior in healthy mice, Alzheimer’s disease and Parkinson’s disease model—a systematic review and meta-analysis. Behav Brain Res 383:112488

    PubMed  Google Scholar 

  40. Brenmoehl J, Albrecht E, Komolka K, Schering L, Langhammer M, Hoeflich A, Maak S (2014) Irisin is elevated in skeletal muscle and serum of mice immediately after acute exercise. Int J Biol Sci 10:338–349

    PubMed  PubMed Central  Google Scholar 

  41. Nygaard H, Slettalokken G, Vegge G, Hollan I, Whist JE, Strand T, Ronnestad BR, Ellefsen S (2015) Irisin in blood increases transiently after single sessions of intense endurance exercise and heavy strength training. PLoS ONE 10:e0121367

    PubMed  PubMed Central  Google Scholar 

  42. Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J Physiol 546:851–858

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91:1447–1531

    CAS  PubMed  Google Scholar 

  44. Kanematsu M, Sato T, Takai H, Watanabe K, Ikeda K, Yamada Y (2000) Prostaglandin E2 induces expression of receptor activator of nuclear factor-κB ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency. J Bone Miner Res 15:1321–1329

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was partly supported by Grants-in-Aid for Scientific Research (C: 19K07310) to N.K. and (C: 20K09514) to H.K. from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

Authors

Contributions

NK and HK contributed to the conception and design of the research. NK, SI, MK, YM and YT performed the experiments. NK analyzed the data. NK and HK interpreted the results of the experiments. NK prepared the figures. NK drafted the manuscript. NK and HK edited and revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Hiroshi Kaji.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All animal experiments were performed in accordance with the guidelines of the National Institutes of Health and the institutional rules for the use and care of laboratory animals at Kindai University. All procedures were approved by the Experimental Animal Welfare Committee of Kindai University (Permit number: KAME-28–016, KAME-2020–011).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 kb)

Supplementary material 2 (DOCX 16 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawao, N., Iemura, S., Kawaguchi, M. et al. Role of irisin in effects of chronic exercise on muscle and bone in ovariectomized mice. J Bone Miner Metab 39, 547–557 (2021). https://doi.org/10.1007/s00774-020-01201-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-020-01201-2

Keywords

Navigation