Advertisement

Aerobic exercise increases irisin serum levels and improves depression and fatigue in patients with relapsing remitting multiple sclerosis: A randomized controlled trial

      Highlights

      • Irisin serum levels increased significantly after aerobic exercise in RRMS patients.
      • Aerobic exercise improves depression, and fatigue in pwMS.
      • Aerobic exercise positively affects information processing and working memory in pwMS.

      Abstract

      Background

      Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease of the central nervous system. Although there is increasing evidence that aerobic exercise has a positive effect on both cognitive and psychological functioning, there is limited evidence for Relapsing-Remitting MS (RRMS) patients. Moreover, it is unclear at what exercise modality and intensity the irisin, the cleaved and circulating form of the exercise-associated membrane protein Fibronectin Type III Domain Containing 5, is induced in patients with MS. This study aimed to investigate the effect of a regular aerobic exercise program on irisin serum level, depression, fatigue, and cognitive performance in patients with MS.

      Methods

      Thirty-two individuals with RRMS were randomized into 2 groups as control and study groups (mean EDSS score 1.69 and 1.97, respectively). While the Study Group received a combined exercise training consisting of three sessions of aerobic exercise and Frenkel Coordination Exercises per week for 6 weeks, the Control Group received only Frenkel Coordination Exercise training. Before and after the study, the cognitive performance of the participants were evaluated with the Paced Auditory Serial Addition Test with 3-second stimulus (PASAT-3), their maximum aerobic capacity with the Fitmate Pro® (VO2max), their fatigue status with the Fatigue Impact Scale (FIS), and their depression status with the Beck Depression Inventory (BDI). Irisin serum levels were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA) test from the serum samples of individuals.

      Results

      Our results revealed that the irisin serum level significantly increased in the Study Group. Significant improvement in aerobic capacity, PASAT-3, FIS, and BDI values was observed in the Study Group compared to the Control Group. When the ΔIrisin, ΔVO2max, ΔFIS, and ΔBDI values between the groups were compared, a significant difference was found in favor of the study group.

      Conclusion

      The aerobic exercise revealed significant changes in depression, fatigue and irisin serum levels in MS patients. We think that this study, in which a significant increase in irisin serum level, significant improvement in depression, cognitive performance and fatigue states were obtained in the Study Group, will be a pioneering study for the future studies aiming to investigate the effects of irisin serum level on these symptoms in detail.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Afzal R.
        • Dowling J.K.
        • McCoy C.E.
        Impact of exercise on immunometabolism in multiple sclerosis.
        J. Clin. Med. 2020; 9 (Published 2020 Sep 21): 3038https://doi.org/10.3390/jcm9093038
        • Alvarenga-Filho H.
        • Sacramento P.M.
        • Ferreira T.B.
        • et al.
        Combined exercise training reduces fatigue and modulates the cytokine profile of T-cells from multiple sclerosis patients in response to neuromediators.
        J. Neuroimmunol. 2016; 293: 91-99https://doi.org/10.1016/j.jneuroim.2016.02.014
        • Boström P.
        • Wu J.
        • Jedrychowski M.P.
        • et al.
        A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
        Nature. 2012; 481 (Published 2012 Jan 11): 463-468https://doi.org/10.1038/nature10777
        • Briken S.
        • Gold S.M.
        • Patra S.
        • et al.
        Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.
        Mult. Scler. 2014; 20: 382-390https://doi.org/10.1177/1352458513507358
        • Compston A.
        • Coles A.
        Multiple sclerosis.
        Lancet. 2008; 372: 1502-1517https://doi.org/10.1016/S0140-6736(08)61620-7
        • Cortés-Martínez A.
        • Matias-Guiu J.A.
        • Pytel V.
        • Montero P.
        • Moreno-Ramos T.
        • Matías-Guiu J.
        What is the meaning of PASAT rejection in multiple sclerosis?.
        Acta Neurol. Scand. 2019; 139: 559-562https://doi.org/10.1111/ane.13090
        • Dalgas U.
        • Ingemann-Hansen T.
        • Stenager E.
        Physical exercise and MS recommendations.
        Int. MS J. 2009; 16: 5-11
        • Dalgas U.
        • Langeskov-Christensen M.
        • Stenager E.
        • Riemenschneider M.
        • Hvid L.G.
        Exercise as medicine in multiple sclerosis-time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
        Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
        • Delezie J.
        • Weihrauch M.
        • Maier G.
        • et al.
        BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle.
        Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 16111-16120https://doi.org/10.1073/pnas.1900544116
        • DeLuca J.
        • Chelune G.J.
        • Tulsky D.S.
        • Lengenfelder J.
        • Chiaravalloti N.D.
        Is speed of processing or working memory the primary information processing deficit in multiple sclerosis?.
        J. Clin. Exp. Neuropsychol. 2004; 26: 550-562https://doi.org/10.1080/13803390490496641
        • de Freitas G.B.
        • Lourenco M.V.
        • De Felice F.G.
        Protective actions of exercise-related FNDC5/Irisin in memory and Alzheimer's disease.
        J. Neurochem. 2020; 155: 602-611https://doi.org/10.1111/jnc.15039
        • Devasahayam A.J.
        • Kelly L.P.
        • Williams J.B.
        • Moore C.S.
        • Ploughman M.
        Fitness shifts the balance of BDNF and IL-6 from inflammation to repair among people with progressive multiple sclerosis.
        Biomolecules. 2021; 11: 504https://doi.org/10.3390/biom11040504
        • Devasahayam A.J.
        • Downer M.B.
        • Ploughman M.
        The effects of aerobic exercise on the recovery of walking ability and neuroplasticity in people with multiple sclerosis: a systematic review of animal and clinical studies.
        Mult. Scler. Int. 2017; 20174815958https://doi.org/10.1155/2017/4815958
        • Diechmann M.D.
        • Campbell E.
        • Coulter E.
        • Paul L.
        • Dalgas U.
        • Hvid L.G.
        Effects of exercise training on neurotrophic factors and subsequent neuroprotection in persons with multiple sclerosis-a systematic review and meta-analysis.
        Brain Sci. 2021; 11 (Published 2021 Nov 12): 1499https://doi.org/10.3390/brainsci111114996
        • Di Liegro C.M.
        • Schiera G.
        • Proia P.
        • Di Liegro I.
        Physical activity and brain health.
        Genes. 2019; 10 (Basel)Published 2019 Sep 17: 720https://doi.org/10.3390/genes10090720
        • Dun S.L.
        • Lyu R.M.
        • Chen Y.H.
        • Chang J.K.
        • Luo J.J.
        • Dun N.J.
        Irisin-immunoreactivity in neural and non-neural cells of the rodent.
        Neuroscience. 2013; 240: 155-162https://doi.org/10.1016/j.neuroscience.2013.02.050
        • Fernández-Muñoz J.J.
        • Cigarán-Méndez M.
        • Navarro-Pardo E.
        • Pérez-de-Heredia-Torres M.
        • Parás-Bravo P.
        • Fernández-de-Las-Peñas C.
        Is the association between health-related quality of life and fatigue mediated by depression in patients with multiple sclerosis? A Spanish cross-sectional study.
        BMJ Open. 2018; 8 (Published 2018 Jan 23)e016297https://doi.org/10.1136/bmjopen-2017-016297
        • Fischer A.
        • Heesen C.
        • Gold S.M.
        Biological outcome measurements for behavioral interventions in multiple sclerosis.
        Ther. Adv. Neurol. Disord. 2011; 4: 217-229https://doi.org/10.1177/1756285611405252
        • Gharakhanlou R.
        • Wesselmann L.
        • Rademacher A.
        • et al.
        Exercise training and cognitive performance in persons with multiple sclerosis: a systematic review and multilevel meta-analysis of clinical trials.
        Mult. Scler. 2021; 27: 1977-1993https://doi.org/10.1177/1352458520917935
        • Gujral S.
        • Aizenstein H.
        • Reynolds C.F.
        • Butters M.A.
        • Erickson K.I
        Exercise effects on depression: possible neural mechanisms.
        Gen. Hosp. Psychiatry. 2017; 49: 2-10https://doi.org/10.1016/j.genhosppsych.2017.04.012
        • Herring M.P.
        • Fleming K.M.
        • Hayes S.P.
        • Motl R.W.
        • Coote S.B.
        Moderators of exercise effects on depressive symptoms in multiple sclerosis: a meta-regression.
        Am. J. Prev. Med. 2017; 53: 508-518https://doi.org/10.1016/j.amepre.2017.04.011
        • Hoang P.D.
        • Lord S.
        • Gandevia S.
        • Menant J.
        Exercise and sports science Australia (ESSA) position statement on exercise for people with mild to moderate multiple sclerosis.
        J. Sci. Med. Sport. 2021; (S1440-2440(21)00214-0)https://doi.org/10.1016/j.jsams.2021.08.015
        • Jodeiri Farshbaf M.
        • Ghaedi K.
        • Megraw T.L.
        • et al.
        Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders?.
        Neuromol. Med. 2016; 18: 1-15https://doi.org/10.1007/s12017-015-8370-x
        • Kalb R.
        • Brown T.R.
        • Coote S.
        • et al.
        Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
        Mult. Scler. 2020; 26: 1459-1469https://doi.org/10.1177/1352458520915629
        • Kara B.
        • Küçük F.
        • Poyraz E.C.
        • Tomruk M.S.
        • İdıman E.
        Different types of exercise in multiple sclerosis: aerobic exercise or pilates, a single-blind clinical study.
        J. Back Musculoskelet. Rehabil. 2017; 30: 565-573https://doi.org/10.3233/BMR-150515
        • Kim J.H.
        • Kim D.Y.
        Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women.
        Exp. Gerontol. 2018; 104: 60-65https://doi.org/10.1016/j.exger.2018.01.024
        • Kim O.Y.
        • Song J.
        The role of irisin in Alzheimer's disease.
        J. Clin. Med. 2018; 7 (Published 2018 Nov 1): 407https://doi.org/10.3390/jcm7110407
        • Kim T.W.
        • Sung Y.H.
        Regular exercise promotes memory function and enhances hippocampal neuroplasticity in experimental autoimmune encephalomyelitis mice.
        Neuroscience. 2017; 346: 173-181https://doi.org/10.1016/j.neuroscience.2017.01.016
        • Kohneshin B.
        • Piree M.
        • Matin Homaee H.
        Aerobic Exercise versus fluoxetine: the effect on depression and cardiac M2 muscarinic receptors in wistar rats.
        Sport Physiol. Manag. Investig. 2020; 12: 131-144
        • Langeskov-Christensen M.
        • Hvid L.G.
        • Jensen H.B.
        • et al.
        Efficacy of high-intensity aerobic exercise on cognitive performance in people with multiple sclerosis: a randomized controlled trial.
        Mult. Scler. 2021; 27: 1585-1596https://doi.org/10.1177/1352458520973619
        • Lourenco M.V.
        • Frozza R.L.
        • de Freitas G.B.
        • et al.
        Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models.
        Nat. Med. 2019; 25: 165-175https://doi.org/10.1038/s41591-018-0275-4
        • Meng D.
        • Welton T.
        • Elsarraj A.
        • et al.
        Dorsolateral prefrontal circuit effective connectivity mediates the relationship between white matter structure and PASAT-3 performance in multiple sclerosis.
        Hum. Brain Mapp. 2021; 42: 495-509https://doi.org/10.1002/hbm.25239
        • Mokhtarzade M.
        • Ranjbar R.
        • Majdinasab N.
        • Patel D.
        • Molanouri Shamsi M.
        Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
        Endocrine. 2017; 57: 262-271https://doi.org/10.1007/s12020-017-1337-y
        • Orban A.
        • Garg B.
        • Sammi M.K.
        • et al.
        Effect of high-intensity exercise on multiple sclerosis function and phosphorous magnetic resonance spectroscopy outcomes.
        Med. Sci. Sports Exerc. 2019; 51: 1380-1386https://doi.org/10.1249/MSS.0000000000001914
        • Ozkul C.
        • Guclu-Gunduz A.
        • Irkec C.
        • et al.
        Effect of combined exercise training on serum brain-derived neurotrophic factor, suppressors of cytokine signaling 1 and 3 in patients with multiple sclerosis.
        J. Neuroimmunol. 2018; 316: 121-129https://doi.org/10.1016/j.jneuroim.2018.01.002
        • Ozkul C.
        • Guclu-Gunduz A.
        • Eldemir K.
        • Apaydin Y.
        • Yazici G.
        • Irkec C.
        Combined exercise training improves cognitive functions in multiple sclerosis patients with cognitive impairment: a single-blinded randomized controlled trial.
        Mult. Scler. Relat. Disord. 2020; 45102419https://doi.org/10.1016/j.msard.2020.102419
        • Pedersen B.K.
        Physical activity and muscle-brain crosstalk.
        Nat. Rev. Endocrinol. 2019; 15: 383-392https://doi.org/10.1038/s41574-019-0174-x
        • Piya M.K.
        • Harte A.L.
        • Sivakumar K.
        • et al.
        The identification of irisin in human cerebrospinal fluid: influence of adiposity, metabolic markers, and gestational diabetes.
        Am. J. Physiol. Endocrinol. Metab. 2014; 306: E512-E518https://doi.org/10.1152/ajpendo.00308.2013
        • Sandroff B.M.
        • Johnson C.L.
        • Motl R.W.
        Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography.
        Neuroradiology. 2017; 59: 61-67https://doi.org/10.1007/s00234-016-1767-x
        • Schumacher M.A.
        • Chinnam N.
        • Ohashi T.
        • Shah R.S.
        • Erickson H.P.
        The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation.
        J. Biol. Chem. 2013; 288: 33738-33744https://doi.org/10.1074/jbc.M113.516641
        • Sousa R.A.L.
        • Improta-Caria A.C.
        • Souza B.S.F.
        Exercise-linked irisin: consequences on mental and cardiovascular health in type 2 diabetes.
        Int. J. Mol. Sci. 2021; 22 (Published 2021 Feb 23): 2199https://doi.org/10.3390/ijms22042199
        • Swank C.
        • Thompson M.
        • Medley A.
        Aerobic exercise in people with multiple sclerosis: its feasibility and secondary benefits.
        Int. J. MS Care. 2013; 15: 138-145https://doi.org/10.7224/1537-2073.2012-037
        • Taul-Madsen L.
        • Connolly L.
        • Dennett R.
        • Freeman J.
        • Dalgas U.
        • Hvid L.G.
        Is aerobic or resistance training the most effective exercise modality for improving lower extremity physical function and perceived fatigue in people with multiple sclerosis? a systematic review and meta-analysis.
        Arch. Phys. Med. Rehabil. 2021; 102: 2032-2048https://doi.org/10.1016/j.apmr.2021.03.026
        • Tu W.J.
        • Qiu H.C.
        • Liu Q.
        • Li X.
        • Zhao J.Z.
        • Zeng X.
        Decreased level of irisin, a skeletal muscle cell-derived myokine, is associated with post-stroke depression in the ischemic stroke population.
        J. Neuroinflamm. 2018; 15: 133https://doi.org/10.1186/s12974-018-1177-6
        • Wang K.
        • Song F.
        • Xu K.
        • et al.
        Irisin attenuates neuroinflammation and prevents the memory and cognitive deterioration in streptozotocin-induced diabetic mice.
        Mediat. Inflamm. 2019; 20191567179https://doi.org/10.1155/2019/1567179
        • Wang S.
        • Pan J.
        Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism.
        Biochem. Biophys. Res. Commun. 2016; 474: 22-28https://doi.org/10.1016/j.bbrc.2016.04.047
        • Wang K.
        • Li H.
        • Wang H.
        • Wang J.H.
        • Song F.
        • Sun Y.
        Irisin exerts neuroprotective effects on cultured neurons by regulating astrocytes.
        Mediat. Inflamm. 2018; 20189070341https://doi.org/10.1155/2018/9070341
        • Wrann C.D.
        • White J.P.
        • Salogiannnis J.
        • et al.
        Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway.
        Cell Metab. 2013; 18: 649-659https://doi.org/10.1016/j.cmet.2013.09.008
        • Zhang W.
        • Chang L.
        • Zhang C.
        • et al.
        Irisin: a myokine with locomotor activity.
        Neurosci. Lett. 2015; 595: 7-11https://doi.org/10.1016/j.neulet.2015.03.069