Effect of the Myokine Irisin on Circadian Rhythm of Voluntary Locomotor Activity in Rats

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Abstract

The endogenous circadian oscillator located in the suprachiasmatic nucleus of mammals, generates its own rhythm, the period of which usually does not correspond exactly to the 24h-duration of the day, and therefore needs to be synchronised with the geophysical daily rhythm of the surrounding word. Within one of the most important non-photic mechanisms of synchronisation of the circadian clock, their entrainment is based on information about the schedule and intensity of physical activity. The role of the key molecular synchronising factor in this mechanism is attributed to the myokine irisin however, the effects of irisin on the behavioural circadian rhythms remain unexplored. In the present work, the effect of three-time intranasal administration of 0.5 μg irisin under constant darkness at different projected moments of three consecutive daily cycles (ZT 2, ZT 6, ZT 10, ZT 14, ZT 18 and ZT 22) on the circadian rhythm of voluntary locomotor activity in a running wheel was studied for the first time in experiments on male Wistar rats. The administration of irisin at ZT 6 induced a statistically significant advanced phase shift of the rhythm acrophase median of 0.60 hours (p < 0.05), accompanied by a decrease in gross locomotor activity by 1666-wheel revolutions per day (p < 0.05). Intranasal administration of irisin at any other moment of the projected daily cycle did not lead to statistically significant phase shift in circadian rhythm or change in total locomotor activity. Irisin did not induce changes in the circadian rhythm period regardless of the time of administration. The obtained results are an experimental confirmation of the role of endogenous irisin as a factor of non-photic synchronization of circadian clock of the suprachiasmatic nucleus, manifested itself in the absence of the main physiological timekeeper – cyclic afferentation from the retinal photoreceptors, in accordance with the daily schedule and intensity of muscle activity within the functional axis “muscles-brain”.

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About the authors

A. N. Inyushkin

Samara National Research University

Author for correspondence.
Email: ainyushkin@mail.ru
Russian Federation, Samara

T. S. Isakova

Samara National Research University

Email: ainyushkin@mail.ru
Russian Federation, Samara

A. T. Konashenkova

Samara National Research University

Email: ainyushkin@mail.ru
Russian Federation, Samara

E. M. Inyushkina

Samara National Research University

Email: ainyushkin@mail.ru
Russian Federation, Samara

A. A. Inyushkin

Samara National Research University

Email: ainyushkin@mail.ru
Russian Federation, Samara

References

  1. Hastings MH, Maywood ES, Brancaccio M (2018) Generation of circadian rhythms in the suprachiasmatic nucleus. Nature Rev Neurosci 19: 273–278. https://doi.org/10.1038/s41583-018-0026-z
  2. Hastings MH, Maywood ES, Brancaccio M (2019) The mammalian circadian timing system and the suprachiasmatic nucleus as its pacemaker. Biology 8: 13. https://doi.org/10.3390/biology8010013
  3. Ashton A, Foster RG, Jagannath A (2022) Photic entrainment of the circadian system. Int J Mol Sci 23: 729. https://doi.org/10.3390/ijms23020729
  4. Weinert D, Gubin D (2022) The impact of physical activity on the circadian system: Benefits for health, performance and wellbeing. Appl Sci 12: 9220. https://doi.org/10.3390/app12189220
  5. Tahara Y, Aoyama S, Shibata S (2017) The mammalian circadian clock and its entrainment by stress and exercise. J Physiol Sci 67: 1–10. https://doi.org/10.1007/s12576-016-0450-7
  6. Zsuga J, More CE, Erdei T, Papp C, Harsanyi S, Gesztelyi R (2018) Blind spot for sedentarism: Redefining the diseasome of physical inactivity in view of circadian system and the irisin/BDNF axis. Front Neurol 9: 818. https://doi.org/10.3389/fneur.2018.00818
  7. Inyushkin AN, Poletaev VS, Inyushkina EM, Kalberdin IS, Inyushkin AA (2024) Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review. J Biomed Res 38: 1–16. https://doi.org/10.7555/JBR.37.20230133
  8. 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 S, Spiegelman BM (2012) A PGC1α-dependent myokine that drives browning of white fat and thermogenesis. Nature 481(7382): 463–468. https://doi.org/10.1038/nature10777
  9. Liu S, Cui F, Ning K, Wang Z, Fu P, Wang D, Xu H (2022) Role of irisin in physiology and pathology. Front Endocrinol 13: 962968. https://doi.org/10.3389/fendo.2022.962968
  10. Wrann CD (2015) FNDC5/irisin – their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast 1: 55–61. https://doi.org/10.3233/BPL-150019
  11. Farshbaf MJ, Alvina K (2021) Multiple roles in neuroprotection for the exercise derived myokine irisin. Front Aging Neurosci 13: 649929. https://doi.org/10.3389/fnagi.2021.649929
  12. Wrann CD, White JP, Salogiannis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (2013) Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 18: 649–659. https://doi.org/10.1016/j.cmet.2013.09.008
  13. Ferrante C, Orlando G, Recinella L, Leone S, Chiavaroli A, Di Nisio C, Shohreh R, Manippa F, Ricciuti A, Vacca M, Brunetti L (2016) Central inhibitory effects on feeding induced by the adipo-myokine irisin. Eur J Pharmacol 791: 389–394. https://doi.org/10.1016/j.ejphar.2016.09.011
  14. Wahab, F., Khan, I. U., Polo, R., Zubair, H., Drummer, C., Shahab, M., Behr R (2019) Irisin in the primate hypothalamus and its effect on GnRH in vitro. J Endocrinol 241: 175–187. https://doi.org/10.1530/JOE-18-0574
  15. Waseem R, Shamsi A, Mohammad T, Hassan MI, Kazim SN, Chaudhary AA, Rudayni HA, Al-Zharani M, Ahmad F, Islam A (2022) FNDC5/irisin: Physiology and pathophysiology. Molecules 27: 1118. https://doi.org/10.3390/molecules27031118
  16. Paoletti I, Coccurello R (2024) Irisin: A multifaceted hormone bridging exercise and disease pathophysiology. Int J Mol Sci 25: 13480. https://doi.org/10.3390/ijms252413480
  17. Yamanaka Y, Hashimoto S, Tanahashi Y, Nishide S, Honma S, Honma K (2010) Physical exercise accelerates reentrainment of human sleep-wake cycle but not of plasma melatonin rhythm to 8-h phase-advanced sleep schedule. Am J Physiol Regul Integr Comp Physiol 298: R681–R691. https://doi.org/10.1152/ajpregu.00345.2009
  18. Hughes ATL, Samuels RE, Bano-Otalora B, Belle MDC, Wegner S, Guilding C, Northeast RC, Loudon ASI, Gigg J, Piggins HD (2021) Timed daily exercise remodels circadian rhythms in mice. Commun Biol 4: 761. https://doi.org/ 10.1038/s42003-021-02239-2
  19. Inyushkin AN, Inyushkina EM, Pavlenko SI, Isakova TS, Konashenkova AT, Romanova ID, Zainulin RA, Inyushkin AA (2023) The effects of irisin on firing activity and spike coding in the rat suprachiasmatic nucleus. Curr Top Pept Protein Res 24: 85–93.
  20. Jud C, Schmutz I, Hampp G, Oster H, Albrecht U (2005) A guideline for analyzing circadian wheel-running behavior in rodents under different lighting conditions. Biol Proced Online 7: 101–116. https://doi.org/10.1251/bpo109
  21. Fukuhara C, Aguzzi J, Bullock N, Tosini G (2005) Effect of long-term exposure to constant dim light on the circadian system of rats. Neurosignals 14: 117–125. https://doi.org/10.1159/000086294
  22. Mrosovsky N (1996) Locomotor activity and non-photic influences on circadian clocks. Biol Rev Cam Philos Soc 71: 343–372. https://doi.org/10.1111/j.1469-185x.1996.tb01278.x
  23. Wang Y, Tian M, Tan J, Pei X, Lu C, Xin Y, Deng S, Zhao F, Gao Y, Gong Y (2022) Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice. J Neuroinflammation 19: 82. https://doi.org/10.1186/s12974-022-02438-6
  24. Zhang W, Chang L, Zhang C, Zhang R, Li Z, Chai B, Li J, Chen E, Mulholland M (2015) Irisin: A myokine with locomotor activity. Neurosci Lett 595: 7–11. https://doi.org/10.1016/j.neulet.2015.03.069.
  25. Siteneski A, Cunha MP, Lieberknecht V, Pazini FL, Gruhn K, Brocardo PS, Rodrigues ALS (2018) Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice. Prog Neuropsychopharmacol Biol Psychiatry 84: 294–303. https://doi.org/10.1016/j.pnpbp.2018.03.004
  26. Ozdemir-Kumral ZN, Akgun T, Hasim C, Hasim C, Ulusoy E, Kalpakcioglu MK, Yuksel MF, Okumus T, Us Z, Akakin D, Yuksel M, Goren Z, Yegen BC (2024) Intracerebroventricular administration of the exercise hormone irisin or acute strenuous exercise alleviates epileptic seizure-induced neuroinflammation and improves memory dysfunction in rats. BMC Neurosci 25: 36. https://doi.org/10.1186/s12868-024-00884-x
  27. Wang S, Pan J (2016) Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism. Biochem Biophys Res Commun 474: 22–28. https://doi.org/10.1016/j.bbrc.2016.04.047
  28. Borisov A, Blagov A, Inyushkin A (2020) Development of tools for processing and analysis of observational data on the activity of laboratory animals. CEUR Workshop Proc 2667: 171–174.
  29. Chen Y, Zhang C, Huang Y, Ma Y, Song Q, Chen H, Jiang G, Gao X (2024) Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway. Adv Drug Deliv Rev 207: 115197. https://doi.org/10.1016/j.addr.2024.115196
  30. Kisku A, Nishad A, Agrawal S, Paliwal R, Datusalia AK, Gupta G, Singh SK, Dua K, Sulakhiya K (2024) Recent developments in intranasal drug delivery of nanomedicines for the treatment of neuropsychiatric disorders. Front Med 11: 1463976. https://doi.org/10.3389/fmed.2024.1463976
  31. Dhuria SV, Hanson LR, Frey WH (2010) Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci 99: 1654–1673. https://doi.org/10.1002/jps.21924
  32. Serova LI, Tillinger A, Alaluf LG, Laukova M, Keegan K, Sabban EL (2013) Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats. Neuroscience 236: 298–312. https://doi.org/10.1016/j.neuroscience.2013.01.040
  33. Laukova M, Alaluf LG, Serova LI, Arango V, Sabban EL (2014) Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats. Endocrinology 155(10): 3920–3933. https://doi.org/10.1210/en.2014-1192
  34. Miyazaki T, Hashimoto S, Masubuchi S, Honma S, Honma K (2001) Phase-advance shifts of human circadian pacemaker are accelerated by daytime physical exercise. Am J Physiol Regul Integr Comp Physiol 281: R197e205. https://doi.org/10.1152/ajpregu.2001.281.1.R197
  35. Youngstedt SD, Elliott JA, Kripke DF (2019) Human circadian phase–response curves for exercise. J Physiol 597: 2253–2268. https://doi.org/0.1113/JP276943
  36. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM (2018) Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175: 1756–1768. e17. https://doi.org/10.1016/j.cell.2018.10.025
  37. Bi J, Zhang J, Ren Y, Du Z, Li T, Wang T, Zhang L, Wang M, Wu Z, Lv Y, Wu R (2020) Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor. J Cell Mol Med 24: 996–1009. https://doi.org/10.1111/jcmm.14811
  38. Oguri Y, Shinoda K, Kim H, Alba DL, Bolus WR, Wang Q, Brown Z, Pradhan RN, Tajima K, Yoneshiro T, Ikeda K, Chen Y, Cheang RT, Tsujino K, Kim CR, Greiner VJ, Datta R, Yang CD, Atabai K, McManus MT, Koliwad SK, Spiegelman BM, Kajimura S (2020) CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 182: 563–577. e20. https://doi.org/10.1016/j.cell.2020.06.021
  39. Estell EG, Le PT, Vegting Y, Kim H, Wrann C, Bouxsein ML, Nagano K, Baron R, Spiegelman BM, Rosen CJ (2020) Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo. eLife 9: e58172. https://doi.org/10.7554/eLife.58172
  40. Decourt C, Evans MC, Inglis MA, Anderson GM (2023) Central irisin signaling is required for normal timing of puberty in female mice. Endocrinology 164: bqac208. https://doi.org/10.1210/endocr/bqac208
  41. Pesce M, La Fratta I., Paolucci T, Grilli A, Patruno A, Agostini F, Bernetti A, Mangone M, Paoloni M, Invernizzi M, de Sire A (2021) From exercise to cognitive performance: Role of irisin. Appl Sci 11: 7120. https://doi.org/10.3390/app11157120
  42. Natalicchio A, Marrano N, Biondi G, Dipaola L, Spagnuolo R, Cignarelli A, Perrini S, Laviola L, Giorgino F (2020) Irisin increases the expression of anorexigenic and neurotrophic genes in mouse brain. Diabetes Metab Res Rev 36: e3238. https://doi.org/10.1002/dmrr.3238
  43. Hashemi MS, Ghaedi K, Salamian A, Karbalaie K, Emadi-Baygi M, Tanhaei S, M H Nasr-Esfahani MH, Baharvand H (2013) Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells. Neuroscience 231: 296–304. https://doi.org/10.1016/j.neuroscience.2012.11.041
  44. Belviranli M, Okudan N, Kabak B, Erdogan M, Karanfilci M (2016) The relationship between brain-derived neurotrophic factor, irisin and cognitive skills of endurance athletes. Phys Sportsmed 44: 290–296. https://doi.org/10.1080/00913847.2016.1196125
  45. Liang FQ, Walline R, Earnest D (1998) Circadian rhythm of brain-derived neurotrophic factor in the rat suprachiasmatic nucleus. Neurosci Lett 242: 89–92. https://doi.org/10.1016/s0304-3940(98)00062-7
  46. Baba K, Ono D, Honma S, Honma K (2008) A TTX-sensitive local circuit is involved in the expression of PK2 and BDNF circadian rhythms in the mouse suprachiasmatic nucleus. Eur J Neurosci 27: 909–916. https://doi.org/10.1111/j.1460-9568.2008.06053.x
  47. Liang FQ, Allen G, Earnest D (2000) Role of brain-derived neurotrophic factor in the circadian regulation of the suprachiasmatic pacemaker by light. J Neurosci 20: 2978–2987. https://doi.org/10.1523/JNEUROSCI.20-08-02978.2000
  48. Takahashi JS, DeCoursey PJ, Bauman L, Menaker M (1984) Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308: 186–188. https://doi.org/10.1038/308186a0
  49. Michel S, Clark JP, Ding JM, Colwell CS (2006) Brain-derived neurotrophic factor and neurotrophin receptors modulate glutamate-induced phase shifts of the suprachiasmatic nucleus. Eur J Neurosci 24: 1109–1116. https://doi.org/10.1111/j.1460-9568.2006.04972.x
  50. Tekin S, Erden Y, Ozyalin F, Cigremis Y, Colak C, Sandal S (2017) The effects of intracerebroventricular infusion of irisin on feeding behaviour in rats. Neurosci Lett 645: 25–32. https://doi.org/10.1016/j.neulet.2017.02.066
  51. Петрова АА, Инюшкин АН (2017) Влияние нейропептида Y на поведенческий циркадианный ритм локомоторной активности крыс. Журн высш нервн деят 67: 786–801. [Petrova AA, Inyushkin AN (2017) Effects of neuropeptide Y on the behavioral circadian rhythm of the locomotor activity in rats. J High Nerv Act 67: 786–801. (In Russ.)]. https://doi.org/10.7868/S0044467718010082

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2. Fig. 1. An example of the response of the circadian rhythm of voluntary locomotor activity to a triple intranasal administration of 0.5 μg irisin at ZT 6. The actigram is presented as a daily (24-hour) raster, so that each row contains data for each consecutive day of the experiment with a total duration of 31 days. The vertical lines correspond to the number of revolutions of the running wheel in consecutive 5-second time intervals. The periods of light on are shown with a light background, the periods of darkness with a dark background. The moments of irisin administration are marked with asterisks and correspond to ZT 6. After the triple administration of irisin, a shift in the rhythm of locomotor activity occurred towards an advance, which in total amounted to 3.19 h in this experiment.

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3. Fig. 2. Statistical data on the effect of triple intranasal administration of 0.5 μg irisin at ZT 6 on the parameters of the circadian rhythm of voluntary locomotor activity. The abscissa axis shows data for 7 days preceding the administration of irisin (Before) and 7 days after administration (Irisin), the ordinate axis shows the period, h (a), acrophase, h (b), and the total activity of treadmill revolutions for 7 days (c).

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4. Fig. 3. An example of an actigram of the circadian rhythm of voluntary locomotor activity under conditions of triple intranasal administration of 0.5 μg irisin in ZT 14. All designations are as in Fig. 1.

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5. Fig. 4. An example of an actigram of the circadian rhythm of voluntary locomotor activity under conditions of three-fold intranasal administration of 2 × 10 μl of water for injection in ZT 6 (control). All designations are as in Fig. 1.

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6. Fig. 5. Phase shifts of the circadian rhythm of voluntary locomotor activity caused by triple intranasal administration of irisin (a) and water for injection (b, control) at different moments of the projected daily cycle. The abscissa axis shows the moment of administration (ZT), the ordinate axis shows the severity of the phase shift, h (positive values – leading shift, negative values – lagging shift). * p < 0.05 (Mann–Whitney rank test).

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