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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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BackgroundAn update on the role of irisin in the regulation of endocrine and metabolic functions
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BackgroundResultInfluentialIs irisin the new player in exercise-induced adaptations or not? A 2017 update
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“Interestingly, protocols of moderate intensity (≤65% VO2max) failed to alter irisin status [23, 28, 37, 39] except in one case [43].”
BackgroundResultInfluentialIrisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process
Zhang, H., Wu, X., Liang, J., Kirberger, M., & Chen, N. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101680 · Cited by 88
Circulating Irisin Concentrations in Rat Models of Thyroid Dysfunction — Effect of Exercise
Samy, D. M., Ismail, C. A., & Nassra, R. A. (2015) · Metabolism · doi:10.1016/j.metabol.2015.01.001 · Cited by 89
Implication of Circulating Irisin Levels with Brown Adipose Tissue and Sarcopenia in Humans
Choi, H. Y., Kim, S., Park, J. W., Lee, N. S., Hwang, S. Y., Huh, J. Y., Hong, H. C., Yoo, H. J., Baik, S. H., Youn, B., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1195 · Cited by 86
Bettariga, F., Taaffe, D. R., Galvão, D. A., Lopez, P., Bishop, C., Markarian, A. M., Natalucci, V., Kim, J.-S., & Newton, R. U. (2024) · Journal of Sport and Health Science · doi:10.1016/j.jshs.2024.04.005 · Cited by 83
“Eleven studies and 17 effect sizes were undertaken for irisin expression 30 min after a single bout of exercise compared to baseline 55,56,62,65,76,83,86,94,96,102,105 (Table 2).”
BackgroundIrisin in humans: recent advances and questions for future research
Boström, P., Fernández‐Real, J. M., & Mantzoros, C. S. (2013) · Metabolism · doi:10.1016/j.metabol.2013.11.009 · Cited by 79
Cell Types Used for Cultured Meat Production and the Importance of Myokines
Shaikh, S., Lee, E. J., Ahmad, K., Ahmad, S. S., Chun, H.-J., Lim, J. H., Lee, Y., & Choi, I. (2021) · Foods · doi:10.3390/foods10102318 · Cited by 81
Murawska‐Ciałowicz, E., Wolański, P. M., Zuwała−Jagiełło, J., Feito, Y., Petr, M., Kokštejn, J., Šťastný, P., & Goliński, D. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17103589 · Cited by 82
“More specifically, changes in irisin concentration were not observed after 45 min of running [35] after 12-weeks of endurance training [36], or after 21-weeks of intensive endurance training [37].”
BackgroundThe role of sex, adiposity, and gonadectomy in the regulation of irisin secretion
Zügel, M., Qiu, S., Laszlo, R., Bosnyák, E., Weigt, C., Müller, D. R., Diel, P. R., Steinacker, J. M., & Schümann, U. (2016) · Endocrine · doi:10.1007/s12020-016-0913-x · Cited by 76
“Exercise intensity appears to be a relevant factor for irisin secretion since no changes in serum irisin levels were detected after low intensity exercise [8, 23].”
BackgroundMuscle Irisin Response to Aerobic vs HIIT in Overweight Female Adolescents
Archundia-Herrera, C., Macias-Cervantes, M., Ruiz-Muñoz, B., Vargas-Ortiz, K., Kornhauser, C., & Perez-Vazquez, V. (2017) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-017-0302-5 · Cited by 72
“However, in other investigations no changes have been found in the expression of irisin (mRNA or protein) [27, 28], the difference could be because in these investigations the exercise was performed at long term.”
BackgroundAmanat, S., Sinaei, E., Panji, M., MohammadporHodki, R., Bagheri-Hosseinabadi, Z., Asadimehr, H., Fararouei, M., & Dianatinasab, A. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.562895 · Cited by 70
Bang, H. S., Seo, D. Y., Chung, Y. M., Oh, K.-M., Park, J. J., Arturo, F., Jeong, S.-H., Kim, N., & Han, J. (2014) · The Korean Journal of Physiology & Pharmacology · doi:10.4196/kjpp.2014.18.5.441 · Cited by 69
“The exercise-mediated increase in circulating irisin was strongly related with improvement of IGF-1 [6-10].”
BackgroundWinn, N. C., Grunewald, Z. I., Liu, Y., Heden, T. D., Nyhoff, L. M., & Kanaley, J. A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0170690 · Cited by 70
Nicolini, C., Michalski, B., Toepp, S. L., Turco, C. V., D'Hoine, T., Harasym, D., Gibala, M. J., Fahnestock, M., & Nelson, A. J. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.03.042 · Cited by 69
Metabolic Health—The Role of Adipo-Myokines
Gräf, C., & Ferrari, N. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246159 · Cited by 70
“no increase in irisin after 8 weeks of intermittent sprint running or after 21 weeks of combined endurance and strength training [50,51].”
BackgroundSerum irisin concentration in women with gestational diabetes
Kuźmicki, M., Telejko, B., Lipińska, D., Pliszka, J., Szamatowicz, M., Wilk, J., Zbucka-Krętowska, M., Laudański, P., Kretowski, A. J., Górska, M., et al. (2014) · Gynecological Endocrinology · doi:10.3109/09513590.2014.920006 · Cited by 66
“Moreover, an association between irisin and insulin sensitivity in humans is still far from clear [3,6–9,11–16].”
Benedini, S., Dozio, E., Invernizzi, P. L., Vianello, E., Banfi, G., Terruzzi, I., Luzi, L., & Romanelli, M. M. C. (2017) · Journal of Diabetes Research · doi:10.1155/2017/1039161 · Cited by 63
Li, D., Huang, F., Lu, W., Jiang, G. ‐., Deng, Y., & Shen, F. (2014) · Acta Physiologica · doi:10.1111/apha.12421 · Cited by 66
“In addition, there is indeed doubt about whether FNDC5/irisin plays a role on humans (Novelle et al. 2013, Pekkala et al. 2013, Elsen et al. 2014).”
BackgroundIrisin: A true, circulating hormone
Pοlyzos, S. A., Mathew, H., & Mantzoros, C. S. (2015) · Metabolism · doi:10.1016/j.metabol.2015.09.001 · Cited by 62
Qiu, S., Bosnyák, E., Treff, G., Steinacker, J. M., Niess, A. M., Krüger, K., Mooren, F. C., Zügel, M., & Schümann, U. (2018) · European Journal of Sport Science · doi:10.1080/17461391.2018.1478452 · Cited by 64
“…on the contrary, several studies noted that acute exercise is not associated with increased circulating irisin (Archundia-Herrera et al., 2017; Lee et al., 2014; Pekkala et al., 2013), which might be due to the differences in the time-points for blood sampling as well as the exercise protocols.”
BackgroundLong-Term Effect of Exercise on Irisin Blood Levels—Systematic Review and Meta-Analysis
Jandova, T., Buendía‐Romero, Á., Polanská, H., Hola, V., Říhova, M., Větrovský, T., Courel‐Ibáñez, J., & Šteffl, M. (2021) · Healthcare · doi:10.3390/healthcare9111438 · Cited by 65
“N/A Özbay [64] Outdoor running (OR) vs. indoorrunning (IR) 18 weeks 4× ↓ * - * IR Palacios-Gonzales [65] School-based physical activityprogram: normal weight 8 months 5× - - Pekkala [15] Endurance training (ET) vs. combined endurance and resistance training (ET + RT) 21 weeks 2× (ET) or 2×(ET) + 2× (RT) - - Table 3.”
BackgroundInfluentialScalzo, R. L., Peltonen, G. L., Giordano, G., Binns, S. E., Klochak, A. L., Paris, H. L. R., Schweder, M. M., Szallar, S. E., Wood, L. M., Larson, D. G., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090696 · Cited by 60
“Ten weeks of endurance exercise increased FNDC5 mRNA [10] in obese men while FNDC5 mRNA did not change following 21 weeks of endurance exercise in normal weight men [49].”
BackgroundLavin, K. M., Coen, P. M., Baptista, L. C. P., Bell, M. B., Drummer, D. J., Harper, S. A., Lixandrão, M. E., McAdam, J. S., O’Bryan, S. M., Ramos, S. V., et al. (2022) · Comprehensive physiology · doi:10.1002/cphy.c200033 · Cited by 78
The Effect of Irisin as a Metabolic Regulator and Its Therapeutic Potential for Obesity
Li, H., Wang, F., Mu, Y., Sun, J., Zhao, Y. C., & Tang, D. (2021) · International Journal of Endocrinology · doi:10.1155/2021/6572342 · Cited by 67
Morelli, C., Avolio, E., Galluccio, A., Caparello, G., Manes, E., Ferraro, S., Rose, D. D., Santoro, M., Barone, I., Catalano, S., et al. (2020) · Nutrients · doi:10.3390/nu12030742 · Cited by 62
“Some authors have reported that chronic exercise did not alter circulating levels of irisin [29,30], however, up to now, the impact of PA intensity levels on irisin concentration in the blood is not completely clarified.”
BackgroundAn update on the validity of irisin assays and the link between irisin and hepatic metabolism
Pοlyzos, S. A., & Mantzoros, C. S. (2015) · Metabolism · doi:10.1016/j.metabol.2015.06.005 · Cited by 55
Dianatinasab, A., Koroni, R., Bahramian, M., Bagheri-Hosseinabadi, Z., Vaismoradi, M., Fararouei, M., & Amanat, S. (2020) · Journal of Exercise Science & Fitness · doi:10.1016/j.jesf.2020.06.004 · Cited by 56
“Similarly, the participants in Norheim et al. ’ s study were obese and prediabetic volunteers, but the Pekkala1 et al. ’ s 29 study focused on healthy man, and their fi ndings did not con fi rm the effects of AE, RE, and CE in inducing PGC-1 a and FNDC5 expression or irisin in healthy men.”
ResultRingleb, M., Javelle, F., Haunhorst, S., Bloch, W., Fennen, L., Baumgart, S., Drube, S., Reuken, P. A., Pletz, M. W., Wagner, H., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202301619r · Cited by 73
Exercise Pills: At the Starting Line
Li, S., & Laher, I. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.08.014 · Cited by 54
“Another consideration is that although there are many studies regarding the effects of exercise on human serum irisin levels [63–66], these studies make conflicting claims about the relationship between circulating irisin levels and exercise [67–74].”
BackgroundDoes IRISIN Have a BRITE Future as a Therapeutic Agent in Humans?
Irving, B. A., Still, C. D., & Argyropoulos, G. A. (2014) · Current Obesity Reports · doi:10.1007/s13679-014-0091-1 · Cited by 56
Dinas, P. C., Lahart, I. M., Timmons, J. A., Svensson, P.-A., Koutedakis, Y., Flouris, A. D., & Metsios, G. S. (2017) · F1000Research · doi:10.12688/f1000research.11107.2 · Cited by 51
Kurdiová, T., Baláž, M., Mayer, A. E., Máderová, D., Belan, V., Wolfrum, C., Ukropec, J., & Ukropcová, B. (2014) · Peptides · doi:10.1016/j.peptides.2014.03.003 · Cited by 52
Pang, M., Yang, J., Rao, J., Wang, H., Zhang, J., Wang, S., Chen, X., & Dong, X. (2018) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.244.93 · Cited by 53
“…between skeletal muscle and peripheral tissues or organs, irisin can increase energy consumption, induce browning of subcutaneous white adipocytes and regulate the metabolism of glucose and lipid via uncoupling protein 1 (UCP-1) (Boström et al. 2012; Pekkala et al. 2013; Wang and Pan 2016).”
BackgroundTanisawa, K., Taniguchi, H., Sun, X., Ito, T., Cao, Z., Sakamoto, S., & Higuchi, M. (2014) · Metabolism · doi:10.1016/j.metabol.2014.01.005 · Cited by 51
“[11] Pekkala S, Wiklund PK, Hulmi JJ, et al.”
BackgroundSerum irisin levels and thyroid function—Newly discovered association
Ruchała, M., Zybek, A., & Szczepanek‐Parulska, E. (2014) · Peptides · doi:10.1016/j.peptides.2014.07.021 · Cited by 51
N-Glycosylation is required for FDNC5 stabilization and irisin secretion
Nie, Y., & Liu, D. (2017) · Biochemical Journal · doi:10.1042/bcj20170241 · Cited by 50
Glucocorticoid receptor positively regulates transcription of FNDC5 in the liver
Kim, H. K., Jeong, Y. J., Song, I.-S., Noh, Y. H., Seo, K. W., Kim, M., & Han, J. (2017) · Scientific Reports · doi:10.1038/srep43296 · Cited by 50
Shirvani, H., & Arabzadeh, E. (2018) · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity · doi:10.1007/s40519-018-0491-4 · Cited by 47
“[12, 41] showed that there was no increase in irisin after 8 weeks of periodic interval training running and after 21 weeks of endurance and strength training, respectively.”
BackgroundDünnwald, T., Melmer, A., Gatterer, H., Salzmann, K., Ebenbichler, C. F., Burtscher, M., Schobersberger, W., & Grander, W. (2019) · International Journal of Sports Medicine · doi:10.1055/a-0828-8047 · Cited by 47
“For instance, irisin levels were found to decease after 12 weeks of endurance training at an intensity of 70 % VO2max [23] but remained unchanged after 21 week of high intensity endurance exercise [26] and after 26 week of low intensity endurance (60 % HR reserve) training in healthy subjects [10].”
BackgroundEffects of Body Weight Reduction on Serum Irisin and Metabolic Parameters in Obese Subjects
Fukushima, Y., Kurose, S., Shinno, H., Thu, H. C. T., Takao, N., Tsutsumi, H., Hasegawa, T., Nakajima, T., & Kimura, Y. (2016) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2016.40.5.386 · Cited by 46
“However, a significant increase in irisin was not found after exercise therapy in non-obese individuals [7,21,22], and no significant changes in irisin occurred in obese patients after 8-week endurance training [23] and 12-week strength and endurance training [24,25].”
Background
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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