Rev Bras Fisiol Exerc. 2025;24:e245633

doi: 10.33233/rbfex.v24i1.5633

REVIEW

Exercise-induced myokines and their role in central nervous system function: a scoping review

Miocinas induzidas pelo exercício físico e suas funções no sistema nervoso central: uma revisão de escopo

 

Pedro Henrique Sobral Neves¹, Paula Araujo2

 

1.    Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil

2.    Universidade Federal da Bahia, Bahia, Brazil

 

Received: May 13, 2025; Accepted: September 9, 2025.

Correspondence: Paula Araujo, E-mail: araujo.pca@gmail.com

 

How to cite

Neves PHS, Paula Araujo P. Exercise-induced myokines and their role in central nervous system function: a scoping review. Rev Bras Fisiol Exerc 2025;24(1):e245633. doi: 10.33233/rbfex.v24i1.5633

 

Abstract

Introduction: The increasing prevalence of neurological diseases is a major global concern. Recently, myokines, molecules secreted by active skeletal muscle, have emerged as potential mediators of the beneficial effects of physical exercise on the central nervous system (CNS), playing a key role in muscle-brain communication. Objective: To review the scientific evidence on the influence of exercise-induced myokines on central nervous system function. Methods: This scoping review included clinical trials evaluating the secretion of exercise-induced myokines and their impact on CNS function in healthy individuals and patients with neurological disorders. Literature searches were conducted in PubMed/Medline, SciELO, and Embase, without time restrictions. Results: Eleven studies met the inclusion criteria. Exercise protocols included aerobic training (seven studies) and strength training (four studies), involving participants aged 23–69 years with or without CNS dysfunctions such as amnesia, Alzheimer’s disease, Parkinson’s disease, and Prader-Willi syndrome. The most investigated myokines were irisin and brain-derived neurotrophic factor (BDNF), although findings were heterogeneous. Some studies demonstrated increased levels of these myokines associated with improvements in cognitive function and balance, while others found no significant changes. Other myokines, including cathepsin B and IGF-1, were linked to synaptic plasticity and neuroprotection. Conclusion: Exercise-induced myokines, particularly irisin and BDNF, appear to modulate CNS function. However, heterogeneity across studies and limited research involving individuals with neurological dysfunctions highlight the need for further investigations with standardized methodologies.

Keywords: central nervous system; exercise, myokine; neuroprotection.

 

Resumo

Introdução: O aumento da prevalência de doenças neurológicas é uma grande preocupação global. Recentemente, as miocinas, moléculas secretadas pelo músculo esquelético em atividade, emergiram como potenciais mediadoras dos efeitos benéficos do exercício físico sobre o sistema nervoso central (SNC), desempenhando papel-chave na comunicação músculo-cérebro. Objetivo: Revisar as evidências científicas sobre a influência das miocinas induzidas pelo exercício físico nas funções do SNC. Métodos: Esta revisão de escopo incluiu ensaios clínicos que avaliaram a secreção de miocinas induzidas pelo exercício físico e seus impactos na função do SNC em indivíduos adultos saudáveis e em pacientes com distúrbios neurológicos. As buscas bibliográficas foram realizadas nas bases PubMed/MEDLINE, SciELO e Embase, sem restrição temporal. Resultados: Onze estudos atenderam aos critérios de inclusão. Os protocolos de exercício abrangeram treinamento aeróbico (sete estudos) e treinamento de força (quatro estudos), envolvendo participantes de 23 a 69 anos, com ou sem disfunções do SNC, como amnésia, doença de Alzheimer, doença de Parkinson e síndrome de Prader-Willi. As miocinas mais investigadas foram a irisina e o fator neurotrófico derivado do cérebro (BDNF), embora os achados tenham sido heterogêneos. Alguns estudos demonstraram elevação desses marcadores associada a ganhos na função cognitiva e equilíbrio, enquanto outros não encontraram mudanças significativas. Outras miocinas, como a catepsina B (CTSB) e o fator de crescimento semelhante à insulina 1 (IGF-1), foram relacionadas à plasticidade sináptica e à neuroproteção. Conclusão: As miocinas induzidas pelo exercício, particularmente irisina e BDNF, parecem modular funções do SNC. Contudo, a heterogeneidade entre os estudos e o número limitado de pesquisas com indivíduos com disfunções neurológicas limitam as conclusões e ressaltam a necessidade de investigações adicionais com metodologias padronizadas.

Palavras-chave: sistema nervoso central; exercício; miocina; neuroproteção.

Introduction

 

Neurological and mental disorders have become a global concern, affecting approximately 700 million people worldwide and accounting for one-third of all non-communicable diseases, according to the World Health Organization (WHO) [1]. In Brazil, recent statistics indicate that 86% of the population experiences some form of mental disorder, such as anxiety or depression [2]. These numbers are expected to rise if contributing factors - such as stress, sedentary lifestyles, childhood trauma, and social isolation - are not effectively addressed.

Given the increasing incidence of central nervous system (CNS) disorders, the scientific community has intensified efforts to identify preventive and therapeutic strategies. In this context, the immune-nervous system interaction has gained prominence, particularly regarding the role of myokines - bioactive molecules released by skeletal muscle during exercise - which appear to exert effects beyond muscle metabolism and homeostasis [3,4,5,6].

Recent studies suggest that brain-muscle crosstalk, mediated by myokines, may influence neurological processes [3,7]. Despite the growing interest in this field, the existing literature lacks a comprehensive analysis of how different exercise protocols influence myokine secretion patterns and their potential effects on CNS function. While the molecular mechanisms underlying these interactions remain to be fully elucidated, a critical gap persists regarding the variability in exercise interventions and the consistency of myokine responses across studies.

In this sense, this scoping review was conducted to address the research question: “What evidence exists regarding the influence of exercise-induced myokines on central nervous system outcomes in adults?”. We aimed to summarize the scientific evidence on the influence of exercise-induced myokines on central nervous system function. Specifically, we seek to identify exercise-induced myokines with potential effects on CNS function; examine the exercise protocols used in relevant studies; and evaluate the impact of myokines on individuals with CNS disorders. Advancing our understanding of these mechanisms will not only expand scientific knowledge but also provide valuable insights for developing novel therapeutic strategies targeting neurological health through exercise-based interventions.

 

Methods

 

This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines [8]. We conducted a scoping review of clinical trials and randomized controlled trials investigating the role of exercise-induced myokines in modulating CNS function.

 

Eligibility criteria

 

Eligible studies were clinical trials and randomized controlled trials that employed physical exercise interventions in adults, assessed myokine secretion, and evaluated CNS-related outcomes. There were no temporal restrictions, and only studies published in English or Portuguese were considered. Exclusion criteria included studies that did not provide sufficient details regarding the exercise protocol (e.g., intensity, duration, frequency, volume), lacked full-text availability, or failed to measure relevant CNS parameters.

 

Search strategy

 

The literature search was conducted in PubMed/Medline, SciELO, and Embase databases using the PICO framework (P: adults; I: physical exercise; C: no-exercise control, pre–post exercise comparisons, or different exercise intensities; O: exercise-induced myokines acting on the central nervous system). The search terms included Myokine, Exerkine, and Exercise, combined with Boolean operators (AND/OR) and MeSH/DeCS terms to ensure comprehensive retrieval of relevant studies.

 

Study selection

 

Based on the eligibility criteria, the study selection process involved two independent reviewers who first screened titles and abstracts, followed by full-text assessment of eligible articles. Disagreements were resolved through discussion, with a third reviewer consulted when necessary. Data extraction was systematically conducted using Excel® spreadsheets.

 

Data extraction and coding

 

Authors extracted data from the final selected articles such as publication year, authorship, participant demographics (age, sex, presence of pathology), exercise protocols (type, frequency, intensity, duration), investigated myokines, changes in myokine secretion patterns, and CNS effects of exercise.

 

Results

 

The database search initially identified 3,716 articles. After duplicate removal and title/abstract screening, 962 studies underwent full-text analysis, from which 11 articles met the inclusion criteria (Figure 1). These studies were published between 2017 and 2023 and included aerobic and/or resistance exercise interventions in individuals aged 23 to 69 years, both healthy and with CNS dysfunctions, such as Alzheimer’s disease, Parkinson’s disease, and Prader-Willi syndrome. Sample sizes varied across studies, ranging from as few as eight participants to as many as 75. Most studies included both sexes, although female participants predominated in several samples. Among the investigated myokines, irisin and brain-derived neurotrophic factor (BDNF) were the most frequently studied, yet the findings were heterogeneous. Other myokines, including Cathepsin B (CTSB) and Insulin-like Growth Factor 1 (IGF-1), were identified as potential modulators of synaptic plasticity and neuroprotection. All studies conducted in healthy subjects applied aerobic training, and only one study measured the acute effect (protocol of one session). The primary outcomes assessed myokine levels, while secondary outcomes included neuroprotection, cognition, executive function, balance, and quality of life, as detailed in Table I.

 

 

Figure 1 – PRISMA-ScR flow diagram illustrating the study selection process

 

Table I – Characteristics of the included studies

 

Five studies assessed irisin in healthy subjects [9,10,11,12,13], reporting conflicting results on its modulation by exercise. While some studies found increased irisin levels following aerobic exercise training, others reported no significant changes, suggesting that exercise intensity and duration may play a role in its regulation. Reycraft et al. [9] found no significant changes in irisin concentration after four weeks of aerobic exercise (one session per week) in older adults. In contrast, Gmiat et al. [10] observed increased irisin levels following 12 weeks of Nordic walking (three sessions per week) in women. Rodziewicz-Flis et al. [11] reported no significant changes in irisin levels after 12 weeks of Nordic walking (three sessions per week) in healthy older adults but noted significant improvements in cognitive functions and physical performance. Nicolini et al. [12] found no changes in serum irisin levels in sedentary but healthy men following an exercise protocol. Meanwhile, Tsai et al. [13] observed increased irisin levels in healthy older adults only after high-intensity interval training (HIIT).

Similarly, BDNF was examined in eight studies, with mixed findings regarding its exercise-induced secretion. Some studies demonstrated elevated BDNF concentrations post-exercise, correlating with cognitive improvements, while others found no significant changes, despite observed enhancements in cognitive function and neuroprotection. De Poli et al. [14], in a study with physically active women, found an increase in BDNF levels after a 49-day acute high-intensity intermittent aerobic exercise protocol (four total sessions). The study also suggested that peripheral BDNF may reduce tension, depression, and anger, regardless of menstrual phase. Reycraft et al. [9] reported an intensity-dependent increase in BDNF levels, associating it with neuroprotection and synaptic plasticity in healthy men. Tsai et al. [13] reported similar BDNF responses after high- and moderate-intensity training, linking exercise to improved neurocognitive performance, though not directly to changes in myokine concentrations. Gmiat et al. [10] observed increased BDNF levels following exercise in healthy women, associating irisin and BDNF increases with cognitive improvement. Nicolini et al. [12] reported increased serum BDNF levels after HIIT training in healthy participants. Kettinen et al. [15] found no changes in plasma BDNF levels after two weeks of aerobic exercise (five sessions per week) in healthy individuals, but reported improvements in cognitive and executive functions, regardless of changes in myokine levels. Rodziewicz-Flis et al. [11] also found no changes in BDNF levels following aerobic exercise. Gaitán et al. [16] observed a decrease in plasma BDNF levels after 26 weeks of aerobic exercise (three sessions per week) in individuals with a family history of Alzheimer’s disease. However, the same study reported improvements in cognitive performance.

Of the 11 included studies, only three specifically investigated individuals with CNS disorders. Zhang et al. [17] reported increased irisin levels following a 12-week multimodal physical training program (52 minutes, twice per week, comprised muscular strength, balance and aerobic training on the cycle ergometer) in patients with Parkinson's disease, associating this increase with improved balance function. Prader-Willi Syndrome patients showed no significant changes in irisin and BDNF levels after 1 session of resistance training [18]. Tsai et al. [19] applied acute aerobic and resistance exercises to men and women with amnesic mild cognitive impairment, detecting a significant increase in serum BDNF levels. Improvements in cognitive-behavioral performance were also observed, assessed via the Flanker test.

Regarding other myokines, one study reported that aerobic training increased plasma CTSB levels, associating this with cognitive improvements in healthy subjects with family history of Alzheimer disease [16]. No significant alterations were found in IL-6, osteonectin, myostatin, or FGF-21 following exercise interventions in healthy and CNS disorders patients [18]. Tsai et al. [19] reported no alterations in serum FGF levels but found a significant increase in serum IGF-1 levels following one session of exercise in.

Differences in study populations, sample sizes, and exercise protocols may account for these inconsistencies reported, emphasizing the complexity of exercise-myokine-CNS interactions. Table II provides a detailed description of exercise protocols and studies outcomes. Table III summarizes changes in the most studied myokines (irisin and BDNF) in healthy subjects according to the exercise protocol.

 

Table II - Exercise protocol description and myokine results

 

Table III - Changes in irisin and BDNF induced by aerobic exercise training in healthy subjects, according to exercise intensity

 

↑ = increase; ↓ = decrease; ↔ = no change.  BDNF: Brain-derived neurotrophic fator.  x: no included study applied this exercise intensity

 

Discussion

 

The findings of this review underscore the influence of physical exercise on myokine secretion and its potential role in CNS function. The most extensively studied myokines, irisin and BDNF, have been linked to cognitive improvements, neuroplasticity, and neuroprotection, yet their secretion patterns appear highly dependent on the specific exercise protocol intensity. In healthy subjects, aerobic exercise of moderate or high intensity, regardless of protocol duration, induced increased secretion of irisin and BDNF. Due to the limited number of studies conducted in individuals with CNS dysfunctions  - and the heterogeneity among them in terms of diagnoses (Parkinson’s disease, Prader-Willi syndrome, and cognitive decline), exercise protocols, and outcome measures - it is not possible to draw definitive conclusions regarding this population.

Studies identified cognitive or mood benefits of exercise in healthy subjects, despite inconsistent changes in myokine concentrations. For instance, while six studies [10,11,13,14,15,16] reported improvements in executive function, memory, mood, and overall cognitive performance, the association between these effects and irisin and BDNF levels remained inconclusive. Cognitive and mood improvements associated with increased myokine levels were observed in all studies that applied high-intensity aerobic exercise [13,14,16]. It is worth noting that Gaitán et al. [16] conducted a progressive intensity protocol and did not find an increase in BDNF levels; however, CTSB levels were associated with cognitive improvements. On the other hand, some studies reported exercise-induced cognitive improvements despite reductions in myokine levels [11] or no significant changes [15]. This discrepancy suggests that exercise intensity may influence these effects, and that exercise can promote neuroplasticity through mechanisms beyond direct myokine modulation - potentially involving other neurotrophic factors, inflammatory pathways, or metabolic adaptations.

Improved cognitive performance associated with increased myokine levels (BDNF, IGF-1) was reported in older adults with amnestic mild cognitive impairment following a single session of aerobic exercise [19]. Beyond cognitive function, other exercise-induced CNS effects were reported in only one study conducted in patients with Parkinson’s disease [17]. Irisin levels increased following a multimodal physical training protocol, and this increase was associated with improved balance function. Recent evidence suggests that postural control, a motor symptom, is linked to cognitive function - a non-motor symptom - in Parkinson’s disease and other neurodegenerative conditions [20,21].

Despite the growing interest in exercise-induced myokines, several knowledge gaps remain. A key observation highlighted by our review is that exercise type and intensity may influence myokine responses. High-intensity training appeared to elicit greater increases in irisin and BDNF, whereas moderate-intensity aerobic exercise yielded more variable results. Resistance training, although less frequently studied, also demonstrated beneficial effects on CNS function - supporting the notion that both aerobic and resistance exercise contribute to brain health. Consistent with our findings, recent reviews suggest a dose–response relationship between exercise intensity and myokine release [22,23]. However, variations in exercise frequency, intensity, duration, and sample characteristics across studies limit the ability to draw definitive conclusions. In spite of the relatively small number of studies, the heterogeneity of findings could be better understood through systematic reviews and meta-analyses focusing on healthy individuals, particularly to quantify the effects of exercise intensity on irisin and BDNF secretion.

Another limitation is that most studies focused on healthy individuals, restricting our understanding of how neurological disorders may modulate myokine secretion and function. Only one study directly compared myokine responses between healthy individuals and those with CNS dysfunctions, reporting no significant differences [18]. This finding underscores the need for comparative research to clarify whether CNS pathologies alter exercise-induced myokine secretion patterns.

Furthermore, most studies assessed only peripheral myokine levels, which may not accurately reflect their activity within the CNS. Future investigations should incorporate neuroimaging techniques, cerebrospinal fluid analysis, and animal models to better elucidate the mechanisms by which exercise-induced myokines affect brain function.

 

Conclusion

 

The findings of this scoping review highlight the potential of physical exercise, particularly aerobic training at moderate to high intensities, to modulate myokine secretion in healthy individuals. Although evidence supporting similar effects in clinical populations remains scarce and inconclusive, these initial observations support future investigations aimed at elucidating the role of exercise-induced myokines as mediators of CNS-related adaptations in both health and disease.

 

Conflict of interest

The authors have no conflicts of interest to declare.

 

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

 

Authors' Contributions

Conceptualization; Data curation; Formal analysis; Writing – original draft: Neves PHS; Conceptualization; Supervision; Writing – review & editing: Araújo P

 

References

 

  1. Alves B, Oliveira M. OMS divulga informe mundial de saúde mental: transformar a saúde mental para todos [Internet]. Biblioteca Virtual em Saúde MS. [cited 2025 Aug 7]. Available from: https://bvsms.saude.gov.br/oms-divulga-informe-mundial-de-saude-mental-transformar-a-saude-mental-para-todos/
  2. Empresa Brasileira de Serviços Hospitalares. Ações realizadas pela Rede Ebserh/MEC buscam conscientizar sobre a importância da saúde mental [Internet]. [cited 2025 Aug 7]. Available from: https://www.gov.br/ebserh/pt-br/comunicacao/noticias/acoes-realizadas-pela-rede-ebserh-mec-buscam-conscientizar-sobre-a-importancia-da-saude-mental
  3. Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383–92. doi: 10.1038/s41574-019-0174-x [Crossref]
  4. Febbraio MA, Pedersen BK. Who would have thought – myokines two decades on. Nat Rev Endocrinol. 2020;16(11):619–20. doi: 10.1038/s41574-020-00408-7 [Crossref]
  5. Bay ML, Pedersen BK. Muscle-organ crosstalk: focus on immunometabolism. Front Physiol. 2020;11:567881. doi: 10.3389/fphys.2020.567881 [Crossref]
  6. Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol. 2022;18(5):273–89. doi: 10.1038/s41574-022-00641-2 [Crossref]
  7. Young MF, Valaris S, Wrann CD. A role for FNDC5/irisin in the beneficial effects of exercise on the brain and in neurodegenerative diseases. Prog Cardiovasc Dis. 2019;62(2):172–8. doi: 10.1016/j.pcad.2019.02.007 [Crossref]
  8. Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169(7):467–73. doi: 10.7326/M18-0850 [Crossref]
  9. Reycraft JT, Islam H, Townsend LK, Hayward GC, Hazell TJ, Macpherson REK. Exercise intensity and recovery on circulating brain-derived neurotrophic factor. Med Sci Sports Exerc. 2020;52(5):1210–7. doi: 10.1249/MSS.0000000000002242 [Crossref]
  10. Gmiat A, Jaworska J, Micielska K, Kortas J, Prusik K, et al. Improvement of cognitive functions in response to a regular Nordic walking training in elderly women – a change dependent on the training experience. Exp Gerontol. 2018;104:105–12. doi: 10.1016/j.exger.2018.02.006 [Crossref]
  11. Rodziewicz-Flis E, Juhas U, Kortas JA, Jaworska J, Bidzan-Bluma I, Babińska A, et al. Nordic walking training in BungyPump form improves cognitive functions and induces changes in amino acids and kynurenine profiles in older adults. Front Endocrinol (Lausanne). 2023;14:123456. doi: 10.3389/fendo.2023.1151184 [Crossref]
  12. Nicolini C, Michalski B, Toepp SL, Turco CV, D'Hoine T, Harasym D, et al. A single bout of high-intensity interval exercise increases corticospinal excitability and BDNF in sedentary healthy males. Brain Res. 2020;437:242–55. doi: 10.1016/j.neuroscience.2020.03.042 [Crossref]
  13. Tsai CL, Pan CY, Tseng YT, Chen FC, Chang YC, Wang TC. Acute effects of high-intensity interval training and moderate-intensity continuous exercise on BDNF and irisin levels and neurocognitive performance in late middle-aged and older adults. Behav Brain Res. 2021;413:113472. doi: 10.1016/j.bbr.2021.113472 [Crossref]
  14. De Poli RAB, Lopes VHF, Lira FS, Zagatto AM, Jimenez-Maldonato A, Antunes BM. Peripheral BDNF and psycho-behavioral aspects are positively modulated by high-intensity intermittent exercise and fitness in healthy women. Sci Rep. 2021;11(1):3810. doi: 10.1038/s41598-021-83072-9 [Crossref]
  15. Kettinen J, Tikkanen H, Hiltunen M, Murray A, Horn N, Taylor WR, Venojärvi M. and biomarker responses in healthy older adults to an 18-hole golf round and different walking types: a randomised cross-over study. BMJ Open Sport Exerc Med. 2023;9(4):e001629. doi: 10.1136/bmjsem-2023-001629 [Crossref]
  16. Gaitán JM, Moon HY, Stremlau M, Dubal DB, Cook DB, Okonkwo OC, et al. Effects of aerobic exercise training on systemic biomarkers and cognition in late middle-aged adults at risk for Alzheimer’s disease. Front Endocrinol (Lausanne). 2021;12:660546. doi: 10.3389/fendo.2021.660181 [Crossref]
  17. Zhang X, Xu S, Hu Y, Liu Q, Liu C, Chai H, et al. Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson’s disease. NPJ Parkinsons Dis. 2023;9(1):7. doi: 10.1038/s41531-023-00453-9 [Crossref]
  18. Hirsch HJ, Gross-Tsur V, Sabag Y, Nice S, Genstil L, Benarroch F, et al. Myokine levels after resistance exercise in young adults with Prader–Willi syndrome (PWS). Am J Med Genet A. 2020;182(1):115–21. doi: 10.1002/ajmg.a.61391 [Crossref]
  19. Tsai CL, Ukropec J, Ukropcová B, Pai MC. An acute bout of aerobic or strength exercise specifically modifies circulating exerkine levels and neurocognitive functions in elderly individuals with mild cognitive impairment. Neuroimage Clin. 2017;17:272–84. doi: 10.1016/j.nicl.2017.10.028 [Crossref]
  20. Tait P, Graham L, Vitorio R, Watermeyer T, Timm EC, O'Keefe J, et al. Neuroimaging and cognitive correlates of postural control in Parkinson’s disease: a systematic review. J Neuroeng Rehabil. 2025;22:24. doi: 10.1186/s12984-024-01539-y [Crossref]
  21. Bae M, Zheng P, VanNostrand M. The effects of balance training on cognitive function in persons with multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord. 2025;94:106274. doi: 10.1016/j.msard.2025.106274 [Crossref]
  22. Zare N, Bishop DJ, Levinger I, Febbraio MA, Broatch JR. Exercise intensity matters: a review on evaluating the effects of aerobic exercise intensity on muscle-derived neuroprotective myokines. Alzheimers Dement (N Y). 2025;11(1):e70056. doi: 10.1002/trc2.70056 [Crossref]
  23. Gao X, Chen Y, Cheng P. Unlocking the potential of exercise: harnessing myokines to delay musculoskeletal aging and improve cognitive health. Front Physiol. 2024;15:1338875. doi: 10.3389/fphys.2024.1338875 [Crossref]