The DOI matches its Crossref record; 91 of the 91 references it cites were found in a registry or an index.
Searching for the exercise factor: is IL-6 a candidate?
Abstract
For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus', 'the work factor' or 'the exercise factor'. In other terms, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Here we discuss the possibility that interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-alpha-production and may thereby inhibit TNF-alpha-induced insulin resistance and atherosclerosis development. We propose that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines'.
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In the citing paper
“The concept of “exercise factor” was based on the fact that muscle contractions engage metabolic and physiological responses in other organs, and that these are not mediated by the nervous system (Pedersen et al., 2003).”
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 Pedersen et al., 2003
In the citing paper
“skeletal muscle has been re-recognized as an active endocrine organ capable of synthesizing and releasing a series of bioactive molecules in response to exercise stimulation, known as “myokines”.”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [6]
In the citing paper
“The discovery of myokines stemmed from the work of Pedersen et al. in 2003, who first demonstrated that skeletal muscle could synthesize and release large amounts of interleukin-6 (IL-6) into the circulation during exercise, thereby regulating the metabolism and function of distant organs [6].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [6]
In the citing paper
“¼ sICAM-1, sVCAM-1”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [618]
In the citing paper
“# sE-selectin”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [618]
In the citing paper
“it is now clear that IL-6 [7] and IL-8 [8] production is upregulated by muscle contraction and that these cytokines may be released from contracting skeletal muscle.”
In the citing paper
“Recently, IL-6 was introduced as the first myokine, defined as a cytokine, which is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
In the citing paper
“We suggest that skeletal muscle is an endocrine organ and that myokines may be involved in mediating the beneficial effects against CNCDs associated with low-grade inflammation.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
In the citing paper
“skeletal muscle has recently been identified as an endocrine organ, which produces and releases cytokines (also called myokines) [18, 19].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
In the citing paper
“A number of studies have demonstrated that working muscle produces IL-6.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
In the citing paper
“Thus muscle biopsies obtained before and after exercise in humans and rats demonstrate very little IL-6 mRNA in resting muscle, but up to a 100-fold increase in exercising skeletal muscle [18, 64, 65].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
In the citing paper
“The magnitude by which plasma IL-6 increases is related to exercise duration, intensity, and muscle mass involved in the mechanical work [13, 18, 60, 62].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [18]
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Yang, J.-F., Huang, W., Lo, C., Lee, M., Lin, C., Shen, P., Dai, Y.-H., Wang, Y.-F., & Chen, T.-W. (2022) · Scientific Reports · doi:10.1038/s41598-022-21443-6 · Cited by 6
The effect of prior exercise onex vivoinduction of heme oxygenase-1 in human lymphocytes
Markovitch, D., Tyrrell, R. M., & Thompson, D. (2007) · Free Radical Research · doi:10.1080/10715760701589230 · Cited by 6
Physical Exercise and Metabolic Reprogramming
Batatinha, H. P., Lira, F. S., Kruger, K., & Rosa Neto, J. C. (2022) · Essential Aspects of Immunometabolism in Health and Disease · doi:10.1007/978-3-030-86684-6_12 · Cited by 5
Zhang, W., He, J., Wang, Y., Jin, H., & Wang, R. (2025) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2025.578574 · Cited by 5
Chen, X., Zhang, W., & Luo, L. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1618612 · Cited by 6
Taylor, A., Ignaszewski, A., Bredin, S. S. D., Hill, J. S., Shellington, E. M., & Warburton, D. E. R. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.752531 · Cited by 6
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Rad, R. S., & Panahzadeh, F. (2023) · Sport Sciences for Health · doi:10.1007/s11332-023-01102-7 · Cited by 5
Sun, Z., Wu, Z., Zhu, L., Li, X., Xu, D., Tian, X., & Mao, D. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1410068 · Cited by 6
“I Want a New Drug”: Exercise as a Pharmacological Therapy
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The Immune System and Inflammation in Type 2 Diabetes
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Characteristics of Skeletal Muscle as a Secretory Organ
Aoi, W. (2017) · Springer eBooks · doi:10.1007/978-981-10-3292-9_9 · Cited by 5
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Fontes, M. T., Costa, T. J. D., de Paula, R. B., de Araújo, F. A., Barros, P. R., Townsend, P., Butler, L., Velázquez, K. T., Hollis, F., Bomfim, G. F., et al. (2024) · Function · doi:10.1093/function/zqae042 · Cited by 4
Protective effect of exercise on animals with sepsis: a systematic review of the existing literature
Yang, N., Jiang, N., Shen, C., Gao, M., Tong, Q., & Sun, J. L. (2025) · BMC Infectious Diseases · doi:10.1186/s12879-025-10557-7 · Cited by 4
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Metadata
- Authors
- Pedersen
- Venue
- Journal of Muscle Research and Cell Motility
- Published
- 2003
- Volume
- 24
- Issue
- 2/3
- Pages
- 113-119
- ISSN
- 0142-4319 (ISSN-L)
- OpenAlex
- W1566764955
- Cited by
- 564
- References
- 91
- Citations by year
- 2026: 19 · 2025: 33 · 2024: 38 · 2023: 52 · 2022: 38 · 2021: 26 · 2020: 31 · 2019: 28 · 2018: 28 · 2017: 32 · 2016: 21 · 2015: 24 · 2014: 23 · 2013: 24 · 2012: 15
- FWCI
- 11.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Muscle Research and Cell Motility (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- interleukin-6, myokines, physical activity, skeletal muscle, muscle contraction, IL-6 expression, glycogen, energy sensing, adipose tissue, lipolysis, lipid oxidation, TNF-α, insulin resistance, atherosclerosis, cytokines
- MeSH terms
- Adipose Tissue, Energy Metabolism, Glucose, Humans, Tumor Necrosis Factor-alpha, Exercise, Interleukin-6, Muscle, Skeletal, Muscle Cells, Lipid Metabolism
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