CoChat
Sign Up
Cited by 1,226Exercise and Physiological ResponsesMuscle Physiology and DisordersAdipokines, Inflammation, and Metabolic Diseases

Muscle–Organ Crosstalk: The Emerging Roles of Myokines

Open access
Severinsen, Mai Charlotte Krogh, Pedersen, Bente Klarlund·2020·Endocrine Reviews
DOI 10.1210/endrev/bnaa016PMC PMC7288608
Open this paper in CoChat — free accountOpen PDF

Abstract

Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases, and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine, or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with, for example, cancer, diabetes, or neurodegenerative diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Skeletal muscle acts as an endocrine organ, releasing myokines in response to exercise that mediate crosstalk with brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, skin, immune system, and tumors. This review updates myokine biology, emphasizing IL-6 and the potential for myokines as exercise biomarkers and therapeutic targets, while noting that specific human functions remain defined for only a small fraction of myokines.

Key findings

  • Myokines are defined as cytokines and other peptides produced, expressed, and released by muscle fibers that exert autocrine, paracrine, or endocrine effects; more than 650 myokines have been identified, but biological function has been described for only 5% of known myokines.
  • IL-6 is a central exercise-induced myokine: it mediates anti-inflammatory effects by increasing IL-1ra and IL-10 and inhibiting endotoxin-induced TNF, delays gastric emptying, stimulates GLP-1 and insulin secretion, contributes to hepatic glucose output during exercise, and in a 12-week randomized controlled trial in abdominally obese humans, IL-6 receptor blockade abolished exercise-induced reduction in visceral adipose tissue mass.
  • Muscle–organ crosstalk includes brain effects via cathepsin B and irisin, which may cross the blood–brain barrier and stimulate BDNF; aerobic exercise training for 3 months increased hippocampal volume by 12% in healthy individuals and by 16% in patients with schizophrenia.
  • Other reported roles include browning of white adipose tissue (irisin, meteorin-like, IL-6), bone regulation (decorin, IL-6, IGF-1, FGF-2 positively; myostatin negatively), skin aging via IL-15, endothelial/revascularization effects via FSTL1, and anticancer effects in mice, where running reduced tumor volume and incidence across 6 tumor models via natural killer cell mobilization and IL-6-dependent redistribution.

Methods

  • Narrative review/update of recent advances in the myokine field; no systematic review protocol, meta-analysis, or primary data collection is described.
  • Synthesizes preclinical and human literature across multiple organs, including cited human infusion studies, exercise trials, and a randomized controlled trial of abdominally obese humans receiving tocilizumab or placebo with aerobic exercise or no exercise for 12 weeks.
  • Main analysis is qualitative synthesis of published findings; no statistical analysis or formal evidence grading is reported.

Limitations

  • The paper states that biological function has been described for only 5% of known myokines; many browning findings are largely restricted to rodents and have not been consistently demonstrated in humans; the exercise-induced rise in plasma irisin in humans is controversial, partly due to unspecific commercial ELISA kits; whether cathepsin B mediates enhanced cognitive function in humans is unknown; the role of meteorin-like in humans remains to be identified; and it remains to be shown that physiological exercise-released IL-6 concentrations have browning effects.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, explicit inclusion criteria, risk-of-bias assessment, and quantitative synthesis, and many mechanistic conclusions rely on animal or preclinical models.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/endrev/bnaa016

Cites

240 of 240 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 156 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Exercise prior to endotoxin totally blunted the increase in circulating levels of TNF-α that was observed during a resting situation.

    “Exercise prior to endotoxin totally blunted the increase in circulating levels of TNF‐α that was observed during a resting situation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Starkie, 2003, Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans, FASEB J. source

      Not checked in the free run.

  • Findingcitation

    Infusion of rhIL-6 prior to endotoxin administration blunts the TNF-α response in humans.

    “It was therefore expected that an infusion of rhIL-6 prior to endotoxin administration would also blunt the TNF‐α response in humans and this was in fact what was found (113).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Starkie, 2003, Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans, FASEB J. source

      Not checked in the free run.

  • Premisecitation

    Skeletal muscle produces and releases interleukin-6 (IL-6) into the circulation.

    “Our finding in 2000 that skeletal muscle produced and released interleukin-6 (IL-6) into the circulation (5)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Steensberg, 2000, Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6, J Physiol. source

      Not checked in the free run.

  • Premisecitation

    IL-6 has multiple metabolic effects in other parts of the body.

    “research during the subsequent years, demonstrating that IL-6 has multiple metabolic effects in other parts of the body (6)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Pedersen, 2008, Muscle as an endocrine organ: focus on muscle-derived interleukin-6, Physiol Rev. source

      Not checked in the free run.

  • Interpretationreasoning

    One or several humoral factors are released from contracting muscles to the blood.

    “Thus, it was obvious that 1 or several humoral factors had to be released from contracting muscles to the blood (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Goldstein, 1961, Humoral nature of hypoglycemia in muscular activity, Am J Physiol. source

      Not checked in the free run.

  • May combine two claims. 36
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    IL-6 mediates the exercise-associated anti-inflammatory effects both acutely with each bout of exercise and as a consequence of training adaptation, including reduction in abdominal adiposity.

    “The myokine IL-6 mediates the exercise-associated anti-inflammatory effects both acutely with each bout of exercise and as a consequence of training adaptation, including reduction in abdominal adiposity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Wedell-Neergaard, 2019, Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial, Cell Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Myokines can be useful biomarkers for monitoring the type and amount of exercise required for the prescription of exercise for people with cancer, diabetes, or neurodegenerative diseases.

    “Myokines can be useful biomarkers for monitoring the type and amount of exercise that are required for the prescription of exercise for people with, for example, cancer, diabetes, or neurodegenerative diseases”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    IL-6 is an exercise factor and skeletal muscle is a secretory organ with endocrine functions.

    “identified IL-6 as an exercise factor and skeletal muscle as a secretory organ with endocrine functions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Steensberg, 2000, Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6, J Physiol. source

      Not checked in the free run.

    • cites [6] Pedersen, 2008, Muscle as an endocrine organ: focus on muscle-derived interleukin-6, Physiol Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myokines mediate communication between muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as within the muscle itself.

    “Myokines mediate communication between muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as within the muscle itself”
    • Also stated in: § Abstract · plain
      “During exercise, myokines signal within the muscle and mediate muscle–organ crosstalk to the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin (7, 29, 30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Pedersen, 2012, Muscles, exercise and obesity: skeletal muscle as a secretory organ, Nat Rev Endocrinol. source

      Not checked in the free run.

    • cites [29] Benatti, 2015, Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation, Nat Rev Rheumatol. source

      Not checked in the free run.

    • cites [30] Pedersen, 2019, Physical activity and muscle-brain crosstalk, Nat Rev Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Myokines exert effects on cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth.

    “Myokines exert their effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 650 myokines have been identified.

    “identifying more than 650 myokines (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Khan, 2019, Myokines: discovery challenges and therapeutic impediments, J Pak Med Assoc.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During exercise, myokines signal within the muscle and mediate muscle-organ crosstalk to the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin.

    “During exercise, myokines signal within the muscle and mediate muscle–organ crosstalk to the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin (7, 29, 30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Pedersen, 2012, Muscles, exercise and obesity: skeletal muscle as a secretory organ, Nat Rev Endocrinol. source

      Not checked in the free run.

    • cites [29] Benatti, 2015, Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation, Nat Rev Rheumatol. source

      Not checked in the free run.

    • cites [30] Pedersen, 2019, Physical activity and muscle-brain crosstalk, Nat Rev Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myostatin is a member of the transforming growth factor β superfamily and negatively regulates myogenesis in an autocrine manner.

    “Myostatin is a member of the transforming growth factor β (TGF-β) superfamily and negatively regulates myogenesis in an autocrine manner (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] McPherron, 1997, Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member, Nature. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LIF is secreted from human cultured myotubes when electrically stimulated and stimulates satellite cell proliferation.

    “LIF protein has been shown to be secreted from human cultured myotubes; when electrically stimulated (50) LIF stimulates satellite cell proliferation (51).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Broholm, 2008, Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle, J Physiol. source

      Not checked in the free run.

    • cites [51] Broholm, 2010, Leukaemia inhibitory factor–an exercise-induced myokine, Exerc Immunol Rev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some myokines exert their effect within skeletal muscle itself and are involved in the regulation of muscle mass.

    “Some myokines exert their effect within skeletal muscle itself and are involved in the regulation of muscle mass (14) (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Lee, 2019, Role of myokines in regulating skeletal muscle mass and function, Front Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 increases both basal glucose uptake and glucose transporter GLUT4 translocation.

    “It is well documented that IL-6 increases both basal glucose uptake and glucose transporter GLUT4 translocation (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Carey, 2006, Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase, Diabetes. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Massive muscle hypertrophy is seen in myostatin knockout mice, cattle, sheep, and dogs, with an increase in fiber cross-sectional area and fiber number.

    “Massive muscle hypertrophy is seen in myostatin knockout mice, cattle, sheep, and dogs (43-45) that demonstrate an increase in fiber cross-sectional area and in fiber number.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] McPherron, 1997, Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member, Nature. source

      Not checked in the free run.

    • cites [44] Mosher, 2007, A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs, PLoS Genet. source

      Not checked in the free run.

    • cites [45] Grobet, 1997, A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle, Nat Genet. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Muscular expression of the IL-6 receptor is elevated in trained human muscle, suggesting that muscular sensitivity to IL-6 is increased by training adaptation.

    “In contrast, the muscular expression of the IL-6 receptor (IL-6R) is elevated in trained human muscle (57), suggesting that muscular sensitivity to IL-6 is increased by training adaptation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Keller, 2005, Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle, J Appl Physiol (1985). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Musclin, LIF, IL-4, IL-6, IL-7, and IL-15 promote muscle hypertrophy, whereas myostatin inhibits muscle hypertrophy.

    “Musclin, LIF, IL-4, IL-6, IL-7, and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Decorin is a myokine regulated by exercise and acts as an antagonist to myostatin.

    “Decorin has been identified as a myokine that is regulated by exercise and acts as an antagonist to myostatin (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Kanzleiter, 2014, The myokine decorin is regulated by contraction and involved in muscle hypertrophy, Biochem Biophys Res Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic loss of IL-6 impairs muscle hypertrophy in vivo, whereas myotube-produced IL-6 stimulates muscle cell proliferation in a paracrine fashion.

    “Genetic loss of IL-6 impaired muscle hypertrophy in vivo, whereas myotube-produced IL-6 stimulated muscle cell proliferation in a paracrine fashion (49).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Serrano, 2008, Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circulating levels of decorin are increased in response to exercise in humans, whereas exercise training reduces levels of myostatin within muscles and blood.

    “Circulating levels of decorin are increased in response to exercise in humans (46), whereas exercise training reduces the levels of myostatin within muscles and blood (47, 48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Kanzleiter, 2014, The myokine decorin is regulated by contraction and involved in muscle hypertrophy, Biochem Biophys Res Commun. source

      Not checked in the free run.

    • cites [47] Saremi, 2010, Effects of oral creatine and resistance training on serum myostatin and GASP-1, Mol Cell Endocrinol. source

      Not checked in the free run.

    • cites [48] Hittel, 2010, Myostatin decreases with aerobic exercise and associates with insulin resistance, Med Sci Sports Exerc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF is expressed in human skeletal muscles but is not released into the circulation and does not work in an endocrine way.

    “Brain-derived neurotrophic factor (BDNF) is also expressed in human skeletal muscles, but BDNF is not released into the circulation and does not work in an endocrine way.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Matthews, 2009, Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase, Diabetologia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical activity and exercise training decrease the risk of dementia and appear to play a role in the treatment of this disease.

    “Physical activity and exercise training decrease the risk of dementia (69-71) and appear to play a role in the treatment of this disease (72).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [69] Aarsland, 2010, Is physical activity a potential preventive factor for vascular dementia? A systematic review, Aging Ment Health. source

      Not checked in the free run.

    • cites [70] Williams, 2010, Preventing Alzheimer’s disease and cognitive decline, Evid Rep Technol Assess (Full Rep).

      Not checked in the free run.

    • cites [71] Santos-Lozano, 2016, Physical activity and Alzheimer disease: a protective association, Mayo Clin Proc. source

      Not checked in the free run.

    • cites [72] Pedersen, 2015, Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases, Scand J Med Sci Sports. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise increases hippocampus volume and blood flow to this part of the brain in rodents and humans.

    “Studies in rodents (81) and humans (82) have shown that exercise increases hippocampus volume and the blood flow to this part of the brain (81).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Kobilo, 2011, Running is the neurogenic and neurotrophic stimulus in environmental enrichment, Learn Mem. source

      Not checked in the free run.

    • cites [82] Erickson, 2011, Exercise training increases size of hippocampus and improves memory, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Muscle contraction is sensed by the brain, suggesting that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function.

    “The finding that muscle contraction is sensed by the brain suggests that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function (7, 29, 30, 83) (Fig. 2).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Pedersen, 2012, Muscles, exercise and obesity: skeletal muscle as a secretory organ, Nat Rev Endocrinol. source

      Not checked in the free run.

    • cites [29] Benatti, 2015, Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation, Nat Rev Rheumatol. source

      Not checked in the free run.

    • cites [30] Pedersen, 2019, Physical activity and muscle-brain crosstalk, Nat Rev Endocrinol. source

      Not checked in the free run.

    • cites [83] Leardini-Tristao, 2019, Beneficial effect of exercise on cognitive function during peripheral arterial disease: potential involvement of myokines and microglial anti-inflammatory phenotype enhancement, J Clin Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise influences neurogenesis in the dentate gyrus and increases synapse plasticity.

    “In particular, exercise has been shown to influence neurogenesis in the dentate gyrus (67, 68) and to increase synapse plasticity (67, 68).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Cotman, 2007, Exercise builds brain health: key roles of growth factor cascades and inflammation, Trends Neurosci. source

      Not checked in the free run.

    • cites [68] Mattson, 2012, Energy intake and exercise as determinants of brain health and vulnerability to injury and disease, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Carbohydrate ingestion during exercise blunted the exercise-induced IL-6 response, the increase in lymphocyte number as well as the cortisol.

    “Carbohydrate ingestion during exercise blunted the exercise-induced IL-6 response, the increase in lymphocyte number as well as the cortisol (204, 205).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [204] Nieman, 1997, Carbohydrate supplementation affects blood granulocyte and monocyte trafficking but not function after 2.5 h or running, Am J Clin Nutr. source

      Not checked in the free run.

    • cites [205] Nehlsen-Cannarella, 1997, Carbohydrate and the cytokine response to 2.5 h of running, J Appl Physiol (1985). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following long-duration exercise of high intensity, the concentration of lymphocytes falls below pre-exercise values whereas the neutrophil number continues to increase.

    “Following long-duration exercise of high intensity, the concentration of lymphocytes falls below pre-exercise values whereas the neutrophil number continues to increase (202, 203).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [202] McCarthy, 1988, The leucocytosis of exercise. A review and model, Sports Med. source

      Not checked in the free run.

    • cites [203] Pedersen, 2000, Exercise and the immune system: regulation, integration, and adaptation, Physiol Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    IL-6 stimulates cortisol production and thereby induces neutrocytosis and lymphopenia.

    “IL-6 stimulates cortisol production and thereby induces neutrocytosis and lymphopenia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antioxidant supplementation totally inhibited the release of IL-6 from exercising human muscle as well as the exercise-induced increase in systemic levels of cortisol.

    “Moreover, antioxidant supplementation totally inhibited the release of IL-6 from exercising human muscle as well as the exercise-induced increase in systemic levels of cortisol (206).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Fischer, 2004, Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle, J Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    IL-6 has anti-inflammatory effects as it inhibits TNF production and stimulates the production of IL-1ra and IL-10.

    “IL-6 has anti-inflammatory effects as it inhibits TNF production and stimulates the production of IL-1ra and IL-10.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infusion of IL-6 to mimic the effects of exercise led to an increase in cortisol and, consequently, a decrease in lymphocyte number accompanied by an increase in neutrophil number.

    “The infusion of IL-6 to mimic the effects of exercise led to an increase in cortisol and, consequently, a decrease in the lymphocyte number accompanied by an increase in neutrophil number (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Steensberg, 2003, IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans, Am J Physiol Endocrinol Metab. source

      Not checked in the free run.

    • Rests on an assumption: IL-6 infusion mimics the effects of exercise.

  • May combine two claims.

    Premisecitation

    FSTL1 has cardioprotective effects in animal models of cardiac injury, promoting endothelial cell function and revascularization through a mechanism that includes nitric oxide synthase.

    “FSTL1 has been shown to possess cardioprotective effects, promoting endothelial cell function and thereby revascularization in animal models of cardiac injury through a mechanism that includes nitric oxide synthase (194, 195).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] Ouchi, 2008, Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism, J Biol Chem. source

      Not checked in the free run.

    • cites [195] Oshima, 2008, Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart, Circulation. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The acute exercise effect on lymphocytes and neutrophils is mediated by adrenaline, but the post-exercise reduction in lymphocyte number and the continuous increase in neutrophil number are mediated by both adrenaline and cortisol.

    “The acute exercise effect on lymphocytes and neutrophils is mediated by adrenaline, but the post-exercise reduction in lymphocyte number and the continuous increase in neutrophil number are mediated by both adrenaline and cortisol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Lack of exercise provokes accumulation of more visceral fat and thereby further enhances inflammation and hence a network of chronic diseases.

    “Lack of exercise provokes accumulation of more visceral fat and thereby further enhances inflammation and hence a network of chronic diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Many cancers are accompanied by systemic low-grade chronic inflammation and such inflammation may drive tumor progression.

    “It is obvious, that many cancers are accompanied by systemic low-grade chronic inflammation and that such inflammation may drive tumor progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a mouse model with conditional expression of the Il6 gene, IL6 derived from adipocytes increased macrophage infiltration of adipose tissue, while IL6 derived from myeloid cells and muscle suppressed it.

    “Using a mouse model with conditional expression of the Il6 gene, it was found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Han, 2020, Regulation of adipose tissue inflammation by interleukin 6, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In humans, exercise training can induce anti-inflammatory effects both acutely with each bout of exercise and via long-term training adaptation including reduction in abdominal adiposity.

    “In humans, exercise training can induce anti-inflammatory effects both acutely with each bout of exercise and via long-term training adaptation including reduction in abdominal adiposity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Accumulation of visceral fat, which is more inflamed than subcutaneous fat, leads to chronic systemic inflammation that predisposes to atherosclerosis, elevated blood lipids, insulin resistance, neurodegeneration, muscle waste, and anemia, factors that are likely to lead to decreased physical activity.

    “Accumulation of visceral fat, which is more inflamed than subcutaneous fat, leads to chronic systemic inflammation that predisposes to atherosclerosis, elevated blood lipids, insulin resistance, neurodegeneration, muscle waste, and anemia, factors that are likely to lead to decreased physical activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exercise training leads to a decrease in visceral and cardiac fat mass and hence a decrease in circulating inflammatory molecules via a mechanism that involves exercise-induced increase in IL-6.

    “Exercise training will lead to a decrease in visceral and cardiac fat mass (136, 138, 221) and hence a decrease in circulating inflammatory molecules via a mechanism that involves exercise-induced increase in IL-6 (136), as described above.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [136] Wedell-Neergaard, 2019, Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial, Cell Metab. source

      Not checked in the free run.

    • cites [138] Christensen, 2019, Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor-dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans, Circulation. source

      Not checked in the free run.

    • cites [221] Christensen, 2019, Effect of aerobic and resistance exercise on cardiac adipose tissues: secondary analyses from a randomized clinical trial, JAMA Cardiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lack of physical activity is associated with a large network of diseases, including type 2 diabetes, cardiovascular diseases, cancer, dementia, and osteoporosis.

    “Lack of physical activity is associated with a large network of diseases, including type 2 diabetes, cardiovascular diseases, cancer, dementia, and osteoporosis (72, 121)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Pedersen, 2015, Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases, Scand J Med Sci Sports. source

      Not checked in the free run.

    • cites [121] Pedersen, 2019, The physiology of optimizing health with a focus on exercise as medicine, Annu Rev Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These hepatokines increase in the circulation after muscle work and appear to be involved in mediating some of the metabolic effects of exercise.

    “These hepatokines increase in the circulation after muscle work and appear to be involved in mediating some of the metabolic effects of exercise.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Weigert, 2019, Hepatokines-a novel group of exercise factors, Pflugers Arch. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepatokines include FGF-21, follistatin, angiopoietin-like protein 4, heat shock protein 72, and IGF binding protein, which are all released from the liver during or immediately after an exercise bout.

    “Hepatokines include FGF-21, follistatin, angiopoietin-like protein 4, heat shock protein 72, and IGF binding protein, which are all released from the liver during or immediately after an exercise bout (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Weigert, 2019, Hepatokines-a novel group of exercise factors, Pflugers Arch. source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    Recombinant human IL-6 infused to mimic exercise-induced plasma IL-6 levels has the same physiological effects as endogenous muscle-derived IL-6 during exercise.

    “Healthy young males underwent 2 hours of bicycle exercise on 3 separate occasions at (1) a relatively high intensity; (2) a low intensity, and (3) a low intensity + infusion of IL-6 to mimic the plasma levels of IL-6 observed during high-intensity exercise.”

  • The paper relies on this without support.

    IL-6 receptor blockade with tocilizumab specifically isolates IL-6's role in exercise-induced visceral fat loss.

    “Abdominally obese humans were randomized to tocilizumab (IL-6 receptor antibody) or placebo during an intervention of 12 weeks with either aerobic exercise or no exercise (136, 137).”
    “However, this effect was abolished by IL-6 receptor blockade (136).”

  • The paper relies on this without support.

    IL-6 infusion mimics the effects of exercise.

    “The infusion of IL-6 to mimic the effects of exercise led to an increase in cortisol and, consequently, a decrease in the lymphocyte number accompanied by an increase in neutrophil number (112).”
3 of 3

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • GLP-1-producing pancreatic cells differ between the text and its cited reference

    Minor

    The gut section attributes IL-6-stimulated GLP-1 secretion to pancreatic β-cells, whereas the title of the cited reference attributes it to alpha cells.

  • IL-6 is said to both stimulate and inhibit appetite

    Minor

    The figure says IL-6 stimulates appetite, while the appetite section says it suppresses feeding and may inhibit appetite.

  • Myostatin is assigned opposite effects on bone resorption

    Minor

    The same paragraph says myostatin reduces osteoclast formation and bone destruction, then calls it a positive regulator of bone resorption.

3 of 3

Cites

Flagged first, then by citations

9 of the 249 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Severinsen, M. C. K., & Pedersen, B. K.
Affiliations
University of Copenhagen (DK)
Corresponding author
Pedersen, Bente Klarlund
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2020-05-11
Volume
41
Issue
4
Pages
594-609
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/endrev/bnaa016
PMC
PMC7288608
OpenAlex
W3024249113
Semantic Scholar
e9cdafc34025c5fb05281385f410991c40c566f0
Cited by
1,226
References
249
Citations by year
2026: 280 · 2025: 274 · 2024: 235 · 2023: 191 · 2022: 138 · 2021: 92 · 2020: 15 · 2018: 1
FWCI
13.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrine Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
Funders
TrygFonden
Topics
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
myokines, skeletal muscle endocrine function, physical activity, paracrine signaling, autocrine signaling, hormone signaling, type 2 diabetes, glucose metabolism, lipid metabolism, white adipose tissue browning, bone formation, endothelial function, muscle hypertrophy, skin anatomy, tumor growth, exercise medicine, exercise biomarkers, neurodegenerative diseases
MeSH terms
Brain, Diabetes Mellitus, Humans, Neoplasms, Exercise, Cytokines, Muscle, Skeletal, Neurodegenerative Diseases, Muscle Cells

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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