Exercise induces a marked increase in plasma follistatin: Evidence that follistatin is a contraction-induced hepatokine
Abstract
Follistatin is a member of the TGF-β super family and inhibits the action of myostatin to regulate skeletal muscle growth. The regulation of follistatin during physical exercise is unclear but may be important because physical activity is a major intervention to prevent age-related sarcopenia. First, healthy subjects performed either bicycle or one-legged knee extensor exercise. Arterial-venous differences were assessed during the one-legged knee extensor experiment. Next, mice performed 1 h of swimming, and the expression of follistatin was examined in various tissues using quantitative PCR. Western blotting assessed follistatin protein content in the liver. IL-6 and epinephrine were investigated as drivers of follistatin secretion. After 3 h of bicycle exercise, plasma follistatin increased 3 h into recovery with a peak of 7-fold. No net release of follistatin could be detected from the exercising limb. In mice performing a bout of swimming exercise, increases in plasma follistatin as well as follistatin mRNA and protein expression in the liver were observed. IL-6 infusion to healthy young men did not affect the follistatin concentration in the circulation. When mice were stimulated with epinephrine, no increase in the hepatic mRNA of follistatin was observed. This is the first study to demonstrate that plasma follistatin is increased during exercise and most likely originates from the liver. These data introduce new perspectives regarding muscle-liver cross talk during exercise and during recovery from exercise.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Follistatin is an exercise-inducible hepatokine that increases transitorily in the recovery period after a bout of exercise.
“Studies in humans have identified follistatin as an exercise-inducible hepatokine that increases transitorily in the recovery period after a bout of exercise [117,134,183].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Regulation of myostatin activity and muscle growth
Lee, S.-J., & McPherron, A. C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151270098 · Cited by 1,616 · see citing works
Hormonal Responses and Adaptations to Resistance Exercise and Training
Kraemer, W. J., & Ratamess, N. A. (2005) · Sports Medicine · doi:10.2165/00007256-200535040-00004 · Cited by 1,389 · see citing works
REGULATION OF MUSCLE MASS BY MYOSTATIN
Lee, S.-J. (2004) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.20.012103.135836 · Cited by 819 · see citing works
Matthews, V. B., Åström, M.-B., Chan, M. H. S., Bruce, C. R., Krabbe, K. S., Prelovsek, O., Åkerström, T., Yfanti, C., Broholm, C., Mortensen, O. H., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1364-1 · Cited by 722 · see citing works
Self-citationCatecholamines and the Effects of Exercise, Training and Gender
Zouhal, H., Jacob, C., Delamarche, P., & Gratas-Delamarche, A. (2008) · Sports Medicine · doi:10.2165/00007256-200838050-00004 · Cited by 553 · see citing works
Interleukin-6 Is a Novel Factor Mediating Glucose Homeostasis During Skeletal Muscle Contraction
Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P., & Pedersen, B. K. (2004) · Diabetes · doi:10.2337/diabetes.53.7.1643 · Cited by 455 · see citing works
Self-citationQuadrupling Muscle Mass in Mice by Targeting TGF-ß Signaling Pathways
Lee, S.-J. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000789 · Cited by 316 · see citing works
Follistatin: A Multifunctional Regulatory Protein
Phillips, D. J., & de Kretser, D. M. (1998) · Frontiers in Neuroendocrinology · doi:10.1006/frne.1998.0169 · Cited by 274 · see citing works
The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor?
Pedersen, B. K., Steensberg, A., Fischer, C. P., Keller, C., Keller, P., Plomgaard, P., Petersen, E. W., & Febbraio, M. A. (2004) · Proceedings of The Nutrition Society · doi:10.1079/pns2004338 · Cited by 273 · see citing works
Self-citationHaidet, A. M., Rizo, L., Handy, C. R., Umapathi, P., Eagle, A., Shilling, C., Boué, D. R., Martin, P. T., Sahenk, Z., Mendell, J. R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709144105 · Cited by 267 · see citing works
Gilson, H., Schakman, O., Kalista, S., Lause, P., Tsuchida, K., & Thissen, J.-P. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00193.2009 · Cited by 248 · see citing works
Zhu, X., Topouzis, S., Liang, L.-F., & Stotish, R. L. (2004) · Cytokine · doi:10.1016/j.cyto.2004.03.007 · Cited by 230 · see citing works
Kraemer, W. J., Volek, J. S., Bush, J. A., Putukian, M., & Sebastianelli, W. J. (1998) · Journal of Applied Physiology · doi:10.1152/jappl.1998.85.4.1544 · Cited by 206 · see citing works
Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease
Rodino‐Klapac, L. R., Haidet, A. M., Kota, J., Handy, C., Kaspar, B. K., & Mendell, J. R. (2009) · Muscle & Nerve · doi:10.1002/mus.21244 · Cited by 194 · see citing works
Antioxidant Supplementation Does Not Alter Endurance Training Adaptation
Yfanti, C., Akerstrom, T. C. A., Nielsen, S. J., Nielsen, A. R., Mounier, R., Mortensen, O. H., Lykkesfeldt, J., Rose, A. J., Fischer, C. P., & Pedersen, B. K. (2010) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3181cd76be · Cited by 182 · see citing works
Self-citationPlomgaard, P., Nielsen, A. R., Fischer, C. P., Mortensen, O. H., Broholm, C., Penkowa, M., Krogh-Madsen, R., Erikstrup, C., Lindegaard, B., Petersen, A. M. W., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0834-6 · Cited by 152 · see citing works
Self-citationDietary supplements affect the anabolic hormones after weight-training exercise
Chandler, R. M., Byrne, H. K., Patterson, J. G., & Ivy, J. L. (1994) · Journal of Applied Physiology · doi:10.1152/jappl.1994.76.2.839 · Cited by 143 · see citing works
Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle
Broholm, C., Mortensen, O. H., Nielsen, S., Akerstrom, T., Zankari, A., Dahl, B., & Pedersen, B. K. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2007.149781 · Cited by 132 · see citing works
Responses of IGF-I to endogenous increases in growth hormone after heavy-resistance exercise
Kraemer, W. J., Aguilera, B. A., Terada, M., Newton, R. U., Lynch, J. M., Rosendaal, G., McBride, J. M., Gordon, S. E., & Häkkinen, K. (1995) · Journal of Applied Physiology · doi:10.1152/jappl.1995.79.4.1310 · Cited by 124 · see citing works
Reame, N. E., Wyman, T. L., Phillips, D. J., de Kretser, D., & Padmanabhan, V. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.9.5130 · Cited by 124 · see citing works
Dieli-Conwright, C. M., Spektor, T. M., Rice, J. C., Sattler, F. R., & Schroeder, E. T. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00590.2009 · Cited by 90 · see citing works
Akerstrom, T. C. A., Birk, J. B., Klein, D. K., Erikstrup, C., Plomgaard, P., Pedersen, B. K., & Wojtaszewski, J. F. P. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.02.057 · Cited by 75 · see citing works
Self-citationReame, N. E. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.83.9.3302 · Cited by 70 · see citing works
The physiology of growth hormone and sport
Widdowson, W. M., Healy, M., Sönksen, P. H., & Gibney, J. (2009) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2009.04.023 · Cited by 69 · see citing works
Serum follistatin levels in women: evidence against an endocrine function of ovarian follistatin
Khoury, R. H., Wang, Q. F., Crowley, W. F., Hall, J. E., Schneyer, A. L., Toth, T. L., MIDGLEY, A. R., & Sluss, P. M. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.4.7714112 · Cited by 63 · see citing works
Role of Follistatin in Promoting Adipogenesis in Women
Flanagan, J. N., Linder, K., Mejhert, N., Dungner, E., Wåhlén, K., Decaunes, P., Rydén, M., Björklund, P., Arver, S., Bhasin, S., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2005 · Cited by 63 · see citing works
Muscle regeneration through myostatin inhibition
Wagner, K. R. (2005) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000184163.61558.ca · Cited by 60 · see citing works
Expression of genes related to myostatin signaling during rat skeletal muscle longitudinal growth
Aoki, M. S., Soares, A. G., Miyabara, E. H., Baptista, I. L., & Moriscot, A. S. (2009) · Muscle & Nerve · doi:10.1002/mus.21426 · Cited by 60 · see citing works
Benabdallah, B., Bouchentouf, M., Rousseau, J., Bigey, P., Michaud, A., Chapdelaine, P., Scherman, D., & Tremblay, J. P. (2008) · Cell Transplantation · doi:10.3727/096368908784153913 · Cited by 51 · see citing works
Inhibins, Activins, and Follistatin in the Aging Female and Male
Hurwitz, J. M., & Santoro, N. (2004) · Seminars in Reproductive Medicine · doi:10.1055/s-2004-831896 · Cited by 39 · see citing works
Myostatin regulates glucose uptake in BeWo cells
Antony, N., Bass, J. J., McMahon, C. D., & Mitchell, M. D. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00331.2007 · Cited by 39 · see citing works
Heinemeier, K. M., Langberg, H., & Kjær, M. (2003) · European Journal of Applied Physiology · doi:10.1007/s00421-003-0881-8 · Cited by 38 · see citing works
Exercise Does Not Influence Myostatin and Follistatin Messenger RNA Expression in Young Women
Jensky, N. E., Sims, J. K., Dieli-Conwright, C. M., Sattler, F. R., Rice, J. C., & Schroeder, E. T. (2010) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e3181c8664f · Cited by 37 · see citing works
Zhang, Y., Kanzaki, M., Mashima, H., Mine, T., & Kojima, I. (1996) · Hepatology · doi:10.1002/hep.510230214 · Cited by 32 · see citing works
The influence of eccentric exercise on mRNA expression of skeletal muscle regulators
Jensky, N. E., Sims, J. K., Rice, J. C., Dreyer, H. C., & Schroeder, E. T. (2007) · European Journal of Applied Physiology · doi:10.1007/s00421-007-0521-9 · Cited by 28 · see citing works
Time course changes in IGFBP-1 after treadmill exercise and postexercise food intake in rats
Anthony, T. G., Anthony, J. C., LEWITT, M. S., Donovan, S. M., & Layman, D. K. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.4.e650 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Muscles, exercise and obesity: skeletal muscle as a secretory organ
Pedersen, B. K., & Febbraio, M. A. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.49 · Cited by 2,909 · see citing works
Self-citationPedersen, B. K. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120033 · Cited by 516 · see citing works
Self-citationProtein nutrition and malnutrition in CKD and ESRD
Zha, Y., & Qian, Q. (2017) · Nutrients · doi:10.3390/nu9030208 · Cited by 292 · see citing works
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
Inter-organ cross-talk in metabolic syndrome
Priest, C., & Tontonoz, P. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0145-5 · Cited by 279 · see citing works
The role of exercise-induced myokines in regulating metabolism
Huh, J. Y. (2018) · Archives of Pharmacal Research · doi:10.1007/s12272-017-0994-y · Cited by 242 · see citing works
Metabolic adaptation in obesity and type ii diabetes: myokines, adipokines and hepatokines
Oh, K.-J., Lee, D., Kim, W., Han, B., Lee, S., & Bae, K.-H. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms18010008 · Cited by 210 · see citing works
Stefanakis, K., Kokkorakis, M., & Mantzoros, C. S. (2024) · Metabolism · doi:10.1016/j.metabol.2024.156057 · Cited by 142 · see citing works
Myostatin: more than just a regulator of muscle mass
Argilés, J. M., Orpí, M., Busquets, S., & López-Soriano, F. J. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.02.001 · Cited by 125 · see citing works
Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio
Hansen, J. S., Rutti, S., Arous, C., Clemmesen, J. O., Secher, N. H., Drescher, A., Gonelle-Gispert, C., Halban, P. A., Pedersen, B. K., Weigert, C., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3668 · Cited by 125 · see citing works
Self-citationGlucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans
Hansen, J. S., Clemmesen, J. O., Secher, N. H., Hoene, M., Drescher, A., Weigert, C., Pedersen, B. K., & Plomgaard, P. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.06.001 · Cited by 123 · see citing works
Self-citationHansen, J. S., Pedersen, B. K., Xu, G., Lehmann, R., Weigert, C., & Plomgaard, P. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1681 · Cited by 106 · see citing works
Self-citationGuo, B., Zhang, Z.-K., Liang, C., Li, J., Liu, J., Lu, A., Zhang, B.-T., & Zhang, G. (2017) · Calcified Tissue International · doi:10.1007/s00223-016-0209-4 · Cited by 96 · see citing works
Effect of Various Exercise Regimens on Selected Exercise-Induced Cytokines in Healthy People
Domin, R., Dadej, D., Pytka, M., Zybek-Kocik, A., Ruchała, M., & Guzik, P. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18031261 · Cited by 79 · see citing works
“In humans under increased energy demand, for example, after acute exercise or prolonged fasting, FST is probably stimulated by an increased glucagon-to-insulin ratio [86,88].”
BackgroundHansen, J., Rinnov, A., Krogh‐Madsen, R., Fischer, C. P., Andreasen, A. S., Berg, R. M. G., Møller, K., Pedersen, B. K., & Plomgaard, P. (2013) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2415 · Cited by 71 · see citing works
Circulating follistatin in relation to energy metabolism
Hansen, J. S., & Plomgaard, P. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.06.002 · Cited by 62 · see citing works
Self-citationIngerslev, B., Hansen, J. S., Hoffmann, C., Clemmesen, J. O., Secher, N. H., Scheler, M., Hrabĕ de Angelis, M., Häring, H. U., Pedersen, B. K., Weigert, C., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.06.018 · Cited by 61 · see citing works
Hepatokines—A novel group of exercise factors
Weigert, C., Hoene, M., & Plomgaard, P. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2216-y · Cited by 57 · see citing works
Self-citationMyokine/Adipokine response to “Aerobic” exercise: Is it just a matter of exercise load?
He, Z., Tian, Y., Valenzuela, P. L., Huang, C., Zhao, J., Hong, P., He, Z., Yin, S., & Lucia, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00691 · Cited by 59 · see citing works
The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
Mouchiroud, M., Camiré, É., Aldow, M., Caron, A., Jubinville, É., Turcotte, L., Kaci, I., Beaulieu, M.-J., Roy, C., Labbé, S. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129492 · Cited by 57 · see citing works
Role of exercise-induced hepatokines in metabolic disorders
Ennequin, G., Sirvent, P., & Whitham, M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00433.2018 · Cited by 54 · see citing works
Singh, R., Braga, M., Reddy, S. T., Lee, S.-J., Parveen, M., Grijalva, V., Vergnes, L., & Pervin, S. (2017) · Endocrinology · doi:10.1210/en.2016-1607 · Cited by 54 · see citing works
Dantas, W. S., Roschel, H., Murai, I. H., Gil, S., Davuluri, G., Axelrod, C. L., Ghosh, S., Newman, S. S., Zhang, H., Shinjo, S. K., et al. (2020) · Diabetes · doi:10.2337/db19-1180 · Cited by 54 · see citing works
Pervin, S., Reddy, S. T., & Singh, R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.653179 · Cited by 42 · see citing works
Regulatory role of exercise-induced autophagy for sarcopenia
Liang, J., Zeng, Z., Zhang, Y., & Chen, N. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2019.110789 · Cited by 33 · see citing works
- Authors
- Hansen, J., Brandt, C., Nielsen, A. R., Hojman, P., Whitham, M., Febbraio, M. A., Pedersen, B. K., & Plomgaard, P.
- Affiliations
- University of Copenhagen (DK)
- The Centre of Inflammation and Metabolism (J.H., C.B., A.R.N., P.H., B.K.P., P.P.), Department of Infectious Diseases and Copenhagen Muscle Research Center, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Baker Heart and Diabetes Institute (AU)
- Corresponding author
- Plomgaard, Peter
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2011-01-01
- Volume
- 152
- Issue
- 1
- Pages
- 164-171
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W1983948326
- Cited by
- 200
- References
- 36
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 13 · 2023: 16 · 2022: 17 · 2021: 11 · 2020: 15 · 2019: 15 · 2018: 21 · 2017: 14 · 2016: 15 · 2015: 14 · 2014: 9 · 2013: 10 · 2012: 8
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Strategiske Forskningsråd (09-067009 and 09-075724, 09–067009, 09 – 075724)
- Sundhed og Sygdom, Det Frie Forskningsråd
- Diabetes Australia Research Trust
- Diabetes Australia
- National Research Foundation
- Danmarks Grundforskningsfond (# 02-512-55, 09-067009, 09-075724)
- Ministério da Ciência, Tecnologia e Inovação
- Novo Nordisk
- Rigshospitalet
- Diabetesforeningen
- Medical Research Council
- Center for Strategic Research
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- follistatin, physical activity, hepatokines, liver, myostatin, TGF-beta superfamily, sarcopenia, interleukin-6, epinephrine, knee extension exercise, swimming training, post-exercise recovery, arteriovenous differences
- MeSH terms
- Adult, Animals, Cell Line, Female, Humans, Liver, Male, Muscle Contraction, Exercise, Muscle, Skeletal, Follistatin, Mice, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
