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Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health?
Open accessAbstract
Key points Contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis and metabolic health, and the associated regulatory role of exercise and PGC‐1α. We analysed the effects of different short‐ and long‐term exercise regimens on muscle FNDC5 and PGC‐1α, and serum irisin, and studied the associations of irisin and FNDC5 with health parameters. FNDC5 and serum irisin did not change after acute aerobic, long‐term endurance training or endurance training combined with resistance exercise (RE) training, or associate with metabolic disturbances. A single RE bout increased FNDC5 mRNA in young, but not older men (27 vs. 62 years). Changes in PGC‐1α or serum irisin were not consistently accompanied by changes in FNDC5. Our data suggest that the effects of exercise on FNDC5 and irisin are not consistent, and that their role in health is questionable. Moreover, the regulatory mechanisms should be studied further. Abstract Recently, contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis, and the associated regulatory role of exercise and PGC‐1α. We therefore evaluated whether muscle FNDC5 mRNA and serum irisin are exercise responsive and whether PGC‐1α expression is associated with FNDC5 expression. The male subjects in the study performed single exercises: (1) 1 h low‐intensity aerobic exercise (AE) (middle‐aged, n= 17), (2) a heavy‐intensity resistance exercise (RE) bout (young n= 10, older n= 11) (27 vs. 62 years), (3) long‐term 21 weeks endurance exercise (EE) training alone (twice a week, middle‐aged, n= 9), or (4) combined EE and RE training (both twice a week, middle‐aged, n= 9). Skeletal muscle mRNA expression was analysed by quantitative PCR and serum irisin by ELISA. No significant changes were observed in skeletal muscle PGC‐1α, FNDC5 and serum irisin after AE, EE training or combined EE + RE training. However, a single RE bout increased PGC‐1α by 4‐fold in young and by 2‐fold in older men, while FNDC5 mRNA only increased in young men post‐RE, by 1.4‐fold. Changes in PGC‐1α or serum irisin were not consistently accompanied by changes in FNDC5. In conclusion, for the most part, neither longer‐term nor single exercise markedly increases skeletal muscle FNDC5 expression or serum irisin. Therefore their changes in response to exercise are probably random and not consistent excluding the confirmation of any definitive link between exercise and FNDC5 expression and irisin release in humans. Moreover, irisin and FNDC5 were not associated with glucose tolerance and being overweight, or with metabolic disturbances, respectively. Finally, factor(s) other than PGC‐1α and transcription may regulate FNDC5 expression.
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“In this study, it was observed that muscle irisin levels were only increased in the young group that performed a single resistance training session, without any changes in irisin serum levels regardless of training.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Pekkala et al., 2013
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“No association was found between levels of FNDC5 and health parameters (Table 1).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Pekkala et al., 2013
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Citations
Cites
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“Yet, the latest reports showed that skeletal muscle FNDC5 expression and circulating irisin levels were decreased in obese patients and associated with insulin sensitivity, and that adipose tissue might secrete irisin in response to exercise (Moreno-Navarrete et al. 2013; Roca-Rivada et al. 2013).”
BackgroundFNDC5/irisin is not only a myokine but also an adipokine
Roca-Rivada, A., Castelao, C., Senin, L. L., Landrove, M. O., Baltar, J., Crujeiras, A. B., Seoane, L. M., Casanueva, F. F., & Pardo, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060563 · Cited by 612 · cited 2×
“Yet, the latest reports showed that skeletal muscle FNDC5 expression and circulating irisin levels were decreased in obese patients and associated with insulin sensitivity, and that adipose tissue might secrete irisin in response to exercise (Moreno-Navarrete et al. 2013; Roca-Rivada et al. 2013).”
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Irisin and Triglyceride Glucose Index as Markers of Dyslipidemia in Young Adults
Sagana, M. K. N., Senghor, K. A. A., Vinodhini, V. M., & Renuka, P. (2022) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-022-01083-3 · Cited by 8
“Interventional studies on exercises of different intensities identified irisin as a beneficial hormone that is released on contraction of skeletal muscle [ 6 ].”
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“…mobilisation, and single-leg NMES (one hour daily for 7 consecutive days), Vanhorebeek et al. [29] reported increased FNDC5 mRNA expression (precursor of irisin, a myokine able to promote myogenic differentiation and myoblast fusion via activation of IL-6 signalling [46,47]) in the stimulated leg.”
Irisina: ¿transmisor de mensajes del Olimpo?
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“The level of FNDC5 mRNA is increased in skeletal muscle in some exercise paradigms.(36) As a key regulator of energy metabolism, PGC-1α can not only regulate glucose metabolism Table 4 (Continued).”
BackgroundRádiková, Ž., Mosna, L., Eckerstorfer, C., Bajer, B., Havranová, A., Imrich, R., Vlček, M., & Penesová, A. (2024) · Endocrine Regulations · doi:10.2478/enr-2024-0013 · Cited by 6
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“However, Pekkala et al (6) reported that irisin levels were not associated Address for Correspondence: Nuray Kanbur MD, Hacettepe İhsan Doğramacı Children’s Hospital, Clinic of Pediatrics, Division of Adolescent Medicine, Ankara, Turkey Phone: +90 312 305 11 60 E-mail: nuraykanbur@hotmail.com ORCID: orcid.org/0000-000…”
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“[14]의 연구에서도 건강한 중년 남성을 대상으로 21주 동안 고강도 유산소 운동을 실시한 후에 혈청 irisin의 농도가 증 가하지 않았다고 보고하였다.”
Li, W., Yang, J.-H., Liu, L., Ding, S., Yu, B., Jiang, L., Yan, N., & Liu, H.-D. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1580029 · Cited by 6
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“Irisin is expressed in response to various forms of exercise, including aerobic exercise [33,34] and resistance training [35,36 ].”
BackgroundIrisin and Metabolic Disorders
Esfahani, M., Baranchi, M., & Goodarzi, M. T. (2015) · Avicenna Journal of Medical Biochemistry · doi:10.17795/ajmb-33230 · Cited by 4
“On the other hand, some studies did not find any association between irisin and glucose homeostasis (18, 19).”
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“However, some other studies observed a decrease in irisin levels after various types of physical activity (62–66) whereas some others reported no changes in irisin levels in different exercise programmes (67, 68).”
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“…is also a possible reason for the differentiation of irisin secretion depending on the type of exercise, as vigorous strength training caused an increase in irisin precursors, i.e., FNDC5 gene mRNA in the muscles of young men, in contrast to aerobic exercise or the entire training process [69].”
Tork, O., Gamal, M., Eshra, M. A., Magdy, S., & Rashed, L. (2016) · Kasr Al Ainy Medical Journal · doi:10.4103/1687-4625.195886 · Cited by 4
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RetractedThe Hormone-like Myokines Irisin as Novel Biomarker for Cardiovascular Risk Stratification”,
Berezin, A. A., Myrnyi, D. P., Myrnyi, S. P., & Berezin, A. Е. (2021) · Pharmacophore · doi:10.51847/cx5vhf76yw · Cited by 4
Effect of Training and Gender on Plasma Irisin, Leptin, and Insulin Levels
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“Moreover, some of these authors [148,151] have suggested that irisin changes in response to exercise might be random and have questioned the notion of irisin being involved in the positive effects of exercise.”
Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study
Averbuch, S., Гайдук, О. А., Yackobovitch‐Gavan, M., Laurian, I., Dorfman, A., Shefer, G., Brener, A., & Lebenthal, Y. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14030793 · Cited by 3
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“Increment in total energy consumption in muscles, reduces body weight and insulin resistance in obese people [4].”
InfluentialLinking Circulating Irisin and Type 2 Diabetes: A Systematic Review and Meta‐Analysis
Aminov, E., Folan, P., & Pisconti, A. (2025) · JCSM Communications · doi:10.1002/rco2.70000 · Cited by 5
“In this regard, it should be noted that irisin not only is released by skeletal muscle during physical activity, but can also promote muscle hypertrophy [41], further stressing the importance of exercise for T2DM patients.”
Skrzep-Poloczek, B., Idzik, M., Michalczyk, K., Chełmecka, E., Kukla, M., Zalejska–Fiolka, J., Poloczek, J., Bogielski, B., Jochem, J., Nowak, D., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12154881 · Cited by 3
“Some studies showed that high-volume resistance exercises engaging all muscle groups led to an increase in the irisin concentration 1 h after exercise [45,47,48], whereas irisin concentration remained unchanged when the exercise engaged only one muscle group [49].”
BackgroundHigh-intensity training and irisin response: A possible molecular cross-talk for irisin response
Li, P., Tong, L., & Bi, X. (2025) · Current Research in Physiology · doi:10.1016/j.crphys.2025.100163 · Cited by 4
“However, the results in the literature are inconsistent because other studies have shown that only an acute bout of HIT increased the expression of irisin when compared to long-term training (Pekkala et al., 2013).”
Soori, R., Asad, M. R., Khosravi, M., & Abbasian, S. (2016) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 3
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“On the other hand, these results disagree with some authors who reported no change in the expression of muscle FNDC5 mRNA after chronic training either in muscle biopsy (Phillips et al., 2012) or in serum of trained subjects (Timmons et al., 2012; Pekkala et al., 2013 and Besse-Patin et al., 2014).”
BackgroundResultBrown and Beige Fat: Therapeutic Potential in Obesity
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Immunohistochemical distribution of irisin in the lungand tongue of Porcupine Hystrix cristata
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Irisin – ‘New Kid on the Block in energy regulation’?
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“(2013), 17 who found no significant change at 15 minutes post-exercise following a lower-volume, isolated knee extension protocol.”
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Bırıncı, Y. Z., Sağdilek, E., Taymur, İ., Budak, E., Beyaz, A., Vatansever, Ş., Pancar, S., Topçu, H., Sarandöl, E., & Şahin, Ş. (2023) · Sport Sciences for Health · doi:10.1007/s11332-023-01152-x · Cited by 2
“According to Pekkala et al. irisin changes in response to acute exercise are probably random and not consistent in humans [35].”
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“It is thought that these different results may be due to reasons such as the duration, intensity and type of exercise performed, or the body mass index and gender differences of the people included in the study, whether they were athletes or not [8].”
The effect of acute exercise and gender on the levels of irisin in elite athletes
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“[22] found no difference in the levels of PGC-1α, FNDC5 and serum irisin in the skeletal muscle after a 1-hour low-intensity aerobic exercise in adult males.”
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Timurkaan, S., Gür, F. M., Tarakçı, B. G., Yalçın, M. H., & Gırgın, M. (2018) · Anatomia Histologia Embryologia · doi:10.1111/ahe.12371 · Cited by 2
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High intensity interval exercise maintains irisin level and reduces body fat in overweight women
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Two‐Way Communication Between Skeletal Muscle and Myokines
Huang, T., Zhou, S., Chen, X., Chen, D., Yu, B., & Huang, Z. (2026) · Cell Biochemistry and Function · doi:10.1002/cbf.70267 · Cited by 1
“Pekkala et al. reported that neither acute nor long‐term exercise increased skeletal muscle FNDC5 expression or serum irisin levels [95], whereas tandem mass spectrometry‐based measurement showed that circulating irisin increased from 3.6 to 4.3 ng/mL after 12 weeks of exercise training [96].”
InfluentialThe Role of Irisin in Gestational Diabetes Mellitus: A Review
Ramin, C. (2014) · Endocrinology & Metabolic Syndrome · doi:10.4172/2161-1017.1000138 · Cited by 1
“[35] Study 1: 17 overweight middle aged men”
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“이에 반하여 저항성 운동의 효과를 관찰한 연구들은 운동 후 Irisin 수준의 증가[6] 또는 변화가 없는[7] 서로 상반된 결과를 나타냈다.”
Shaker, M., Khamisipour, G., Sadeghipour, H., Zar, A., Naeimi, B., & Akbarzadeh, S. (2021) · Comparative Exercise Physiology · doi:10.3920/cep210031 · Cited by 1
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Strategies to activate brown adipose tissue in humans
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Chronic Exercise Training and Circulating Irisin in Adults
Meta-Analysis, A. (2015)
Is there a relationship between delivery mode and serum irisin levels in pregnant women?
Haberal, E. T., Ulu, İ., Özcan, C., Gök, G. A., Kıran, G., & Kücür, M. (2017) · Journal of Laboratory Medicine · doi:10.1515/labmed-2017-0042
“Irisin results differ according to the irisin assays [22], and some irisin ELISA kits have been validated [12, 23].”
BackgroundHejazi, K., Hosseini, S. R. A., Fathi, M., & Ziaaldini, M. M. (2018) · Report of Health Care
Abdellah, R. K., El‐Beih, N. M., Morsy, F. A., Abdel-Wahhab, K. G., & El‐Hussieny, E. A. (2021) · Egyptian Pharmaceutical Journal · doi:10.4103/epj.epj_50_20
Exercise as part of anxiety coping management in the Covid-19 pandemic era
Agustiningsih, D., & Wibowo, R. A. (2021) · Journal of the Medical Sciences (Berkala Ilmu Kedokteran) · doi:10.19106/jmedsci005303202109
ACUTE EFFECT OF BLOOD FLOW RESTRICTED RESISTANCE EXERCISE ON IRISIN AND SEX HORMONES
Ercan, S., Canbulut, A., Şirin, F. B., Arıcan, H. M., Oğul, A., & Çetin, C. (2022) · Current Perspectives on Health Sciences · doi:10.58208/cphs.1195891
Prastickho, A. D., Merawati, D., & Sugiharto, S. (2023) · COMPETITOR Jurnal Pendidikan Kepelatihan Olahraga · doi:10.26858/cjpko.v15i2.47705
Kim, Y., Lee, G., Yoon, J., & Kim, K. (2023) · Exercise Science · doi:10.15857/ksep.2023.00374
“However, since the RT and Soy+RT groups did not show a significant difference from the Con group in this study, it can be suggested that the expression pattern of PGC-1α protein in the muscle may differ depending on the exercise type and intake conditions [28,30].”
BackgroundMaleki, A. H., & Hosseini, M. (2022) · Journal of Sports Physiology and Athletic Conditioning · doi:10.61186/jspac.36659.2.4.3
KOMBİNE EGZERSİZLERİN İRİSİN, İNSÜLİN, LİPİD PROFİLİ VE VÜCUT BİLEŞİMİ ÜZERİNE ETKİSİ
Karagöz, Ş., Yıldırım, İ., Ersöz, Y., Koca, H. B., & Köken, T. (2024) · Kocatepe tıp dergisi. · doi:10.18229/kocatepetip.1138553
Riwayadi, D., Ambardini, R. L., Sutapa, P., Hardianto, D., Ali, S. K. S., Karakauki, M., Aryanto, S. J., Pratama, K. W., Utami, D., & Kristianto, A. (2024) · doi:10.56984/8zg01a8q3s7
Mohammed, E., & Hassan, E. A. (2024) · Indian Journal of Surgery · doi:10.1007/s12262-024-04257-w
İrisin Hormonunun Sağlık ve Enerji Homeostazı Üzerine Etkileri
Kartal, M. E., & Baran, Ö. (2024) · Turkish Journal of Diabetes and Obesity · doi:10.25048/tudod.1516025
Heydari, S., Ahmadi, B., Movahed, A., Khamisipour, G., Naeimi, B., Shaker, M., Alizadeh, M., & Akbarzadeh, S. (2025) · Sport Sciences for Health · doi:10.1007/s11332-025-01377-y
“In Satu Pekkala et al. study, FNDC5 gene expression of skeletal muscle was only increased in young subjects who underwent high-intensity resistance training [40].”
Gharaat, M., & Karami, S. (2025) · مجله دانشگاه علوم پزشکی اراک · doi:10.61186/jams.28.1.24
Physical exercise and irisin: managing obesity and related comorbidities
Negroiu, C. E., Tudorașcu, I., Dănoiu, S., Pădureanu, V., Godeanu, S., Dănoiu, R., Ungureanu, A., Beznă, M. C., & Moise, C. G. (2025) · Romanian Journal of Morphology and Embryology · doi:10.47162/rjme.66.2.05 · Cited by 1
Leite, P. L. D. A., Maciel, L. A., Patricio, R. C. B., de Lima, W. S., Silva, C. V. D. S., Aguiar, S. D. S., Neto, I. V. D. S., Rosa, T. D. S., Ramos, I. V., Campbell, C., et al. (2026) · International Journal of Sports Medicine · doi:10.1055/a-2876-1454
Marano, L., Missaglia, S., Martegani, E., Dio, C. D., Catellani, P., Marchetti, A., Vezzoli, M., Tavian, D., & Cereda, F. (2026) · International Journal of Sport and Exercise Psychology · doi:10.1080/1612197x.2026.2701822
The Effect of Progressive Resistance Training on Irisin and Cognition in Healthy Older Adults
Newman, J. E., King, I. N., Flemming, N., Buhmann, R., Rose, G. L., Broadhouse, K. M., Jenkins, D. G., Askew, C. D., & Schaumberg, M. A. (2026) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000005477
Gao, R., Zhang, Y., & Quan, L. (2026) · Comprehensive physiology · doi:10.1002/cph4.70248
“Pekkala et al. reported that high-volume resistance exercise for each muscle group uniformly increased muscular irisin levels (Perakakis et al. 2017; Pekkala et al. 2013; Guo, Shen, et al. 2024).”
Aljawini, N., Habib, S. S., & Al-Regaiey, K. (2026) · Nutrients · doi:10.3390/nu18213531
Metadata
- Authors
- Pekkala, S., Wiklund, P. K., Hulmi, J. J., Ahtiainen, J. P., Horttanainen, M., Pöllänen, E., Mäkelä, K. A., Kainulainen, H., Häkkinen, K., Nyman, K., Alén, M., Herzig, K., & Cheng, S.
- Affiliations
- University of Jyväskylä (FI)
- University of Oulu (FI)
- Central Finland Health Care District (FI)
- Oulu University Hospital (FI)
- Kuopio University Hospital (FI)
- Corresponding author
- Pekkala, Satu
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2013-10-04
- Volume
- 591
- Issue
- 21
- Pages
- 5393-5400
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC3936375
- OpenAlex
- W1932144823
- Cited by
- 292
- References
- 16
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 18 · 2023: 12 · 2022: 33 · 2021: 25 · 2020: 16 · 2019: 17 · 2018: 31 · 2017: 17 · 2016: 16 · 2015: 34 · 2014: 35 · 2013: 8
- FWCI
- 21.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Jyväskylä University Digital Archive (University of Jyväskylä) (submittedVersion)
- Funders
- Diabetestutkimussäätiö
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FNDC5, irisin, PGC-1α, skeletal muscle gene expression, resistance training, endurance training, aerobic exercise, exercise training, energy homeostasis, metabolic health, aging, age differences, serum biomarkers, exercise response variability, metabolic disorders, diabetes mellitus, cardiovascular risk factors, oxidative stress, insulin sensitivity, adipokines
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adult, Age Factors, Aged, Fibronectins, Humans, Male, Middle Aged, Physical Endurance, RNA, Messenger, Transcription Factors, Transcription, Genetic, Case-Control Studies, Muscle, Skeletal, Resistance Training
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