CoChat
Sign Up
Cited by 927Exercise and Physiological ResponsesAdipokines, Inflammation, and Metabolic DiseasesMuscle Physiology and Disorders

Exerkines in health, resilience and disease

Open access
Chow, Lisa S., Gerszten, Robert E., Taylor, Joan M., Pedersen, Bente K., van Praag, Henriette, Trappe, Scott, Febbraio, Mark A., Galis, Zorina S. +17 more·2022·Nature Reviews Endocrinology
DOI 10.1038/s41574-022-00641-2PMC PMC9554896
Open this paper in CoChat — free accountOpen PDF

Abstract

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. Exerkines are signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. Although the benefits of exercise in enhancing health and treating disease are well-acknowledged, the molecular mechanisms underlying exercise-associated benefits remain ill-defined and are actively being investigated. ‘Exerkines’ encompass a broad variety of signalling moieties released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. Exerkines can come in many forms, such as hormones, metabolites, proteins and nucleic acids; interest is increasing in moving beyond singular changes of specific factors to profiling exerkine alterations using ‘omics’ platforms. There is burgeoning interest in the role of extracellular vesicles, which are membranous structures released from cells, in serving as important carriers of molecular signals and drivers of inter-organ crosstalk related to exercise. Multiple organ systems, including the cardiometabolic system, nervous system and immune system, produce exerkines and are influenced by exerkines, which probably contributes to the pleiotropic and variable response to exercise. Emerging research on exerkines suggests multiple promising avenues for translational research and therapeutic modulation to capture exercise-associated benefits; enhanced rigour in experimental design will facilitate comparison between studies. Although the benefits of exercise in enhancing health and treating disease are well-acknowledged, the molecular mechanisms underlying exercise-associated benefits remain ill-defined and are actively being investigated. ‘Exerkines’ encompass a broad variety of signalling moieties released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. Exerkines can come in many forms, such as hormones, metabolites, proteins and nucleic acids; interest is increasing in moving beyond singular changes of specific factors to profiling exerkine alterations using ‘omics’ platforms. There is burgeoning interest in the role of extracellular vesicles, which are membranous structures released from cells, in serving as important carriers of molecular signals and drivers of inter-organ crosstalk related to exercise. Multiple organ systems, including the cardiometabolic system, nervous system and immune system, produce exerkines and are influenced by exerkines, which probably contributes to the pleiotropic and variable response to exercise. Emerging research on exerkines suggests multiple promising avenues for translational research and therapeutic modulation to capture exercise-associated benefits; enhanced rigour in experimental design will facilitate comparison between studies.

AI snapshot

Written from the paper’s full text.

TL;DR

This Review summarizes exerkine biology—signalling molecules released by acute and/or chronic exercise—and their roles in cardiovascular, metabolic, immune and neurological health. It argues that exerkines are promising mediators, biomarkers and possible therapeutics, but that human translation is limited by inconsistent acute versus chronic responses, animal–human discrepancies and study variability.

Key findings

  • Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise that act through endocrine, paracrine and/or autocrine pathways; they include myokines, cardiokines, hepatokines, adipokines, batokines and neurokines, and can be cytokines, nucleic acids, lipids or metabolites.
  • Exercise response is highly variable: in the HERITAGE family study, 20 weeks of supervised aerobic training in 481 sedentary, healthy, white adults from 98 two-generation families yielded a maximal heritability estimate of roughly 47% for aerobic capacity response, with ~20% non-response and 7–15% adverse response in systolic blood pressure, HDL cholesterol, triglycerides and insulin.
  • Acute exercise can broadly alter molecular profiles: in humans across insulin sensitivity (n = 36), an acute treadmill bout altered >50% of measured molecules across lipidomics, metabolomics, proteomics, transcriptomics and epigenomics; after a marathon, plasma IL-6, IL-1RA, IL-10 and TNF peaked 1–2 h after exercise and remained elevated for ~4 h.
  • Preclinical cancer data are striking: in tumour-bearing mouse models across five tumour models, voluntary wheel running reduced tumour incidence and growth by more than 60% versus sedentary mice, with adrenaline and IL-6 inducing natural killer cell mobilization and tumour infiltration.

Methods

  • This is a narrative Review based on a 2020 virtual 2-day NIH workshop that convened 21 international experts on “Exerkines in Health, Resilience, and Diseases”; the workshop executive summary laid the foundation for the article.
  • It synthesizes human and animal exercise studies, tissue-specific exerkine literature, omics platforms, extracellular vesicle methods, and ongoing consortium work such as MoTrPAC (estimated 2,280 human participants; ~800 animals; acute and chronic exercise designs).
  • No primary experimental data, systematic search strategy or meta-analysis is reported; the paper is a conceptual and literature-based synthesis with tables and figures.

Limitations

  • The paper states that contentious questions remain, including lack of consistency between acute and chronic exercise responses, discrepancies between humans and animal models, and interpretation challenges from variability in outcomes and sampling.
  • It states that evidence for exercise benefits on cognition remains variable, probably owing to the lack of randomized controlled trials throughout the lifespan with standardized exercise interventions and comparable cognitive assessment methods.
  • Evident from the text: as a narrative Review, it does not systematically appraise or meta-analyze the cited literature, and many mechanistic claims rely on animal models or small human studies, limiting causal inference and generalizability.

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

Integrity signals

Registry

Crossref · 10.1038/s41574-022-00641-2

Cites

204 of 204 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 212 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    About 7-15% of individuals showed an adverse response in systolic blood pressure and fasting HDL cholesterol, triglycerides and insulin after chronic exercise.

    “7–15% of individuals demonstrated an ‘adverse response’ regarding alterations in systolic blood pressure, as well as in fasting levels of HDL cholesterol, triglycerides and insulin25,26.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Bouchard, C. et al. Familial aggregation of V˙O2max response to exercise training: results from the HERITAGE Family Study. J. Appl. Physiol. 87, 1003–1008 (1999). source

      Not checked in the free run.

    • cites [26] Bouchard, C. et al. Adverse metabolic response to regular exercise: is it a rare or common occurrence? PLoS ONE 7, e37887 (2012). source

      Not checked in the free run.

  • Premisereasoning

    The acute exerkine response does not necessarily parallel the chronic exerkine response.

    “Notably, the acute exerkine response does not necessarily parallel the chronic exerkine response (Supplementary Table 1).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A 2022 study provided an atlas of time-dependent effects of exercise across multiple tissues after a single treadmill exercise bout.

    “a study published in 2022, which included an atlas describing the time-dependent effects of exercise across multiple tissues after a single bout of treadmill exercise24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Sato, S. et al. Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis. Cell Metab. 34, 329–345.e8 (2022). Using a mouse model, this paper presents a detailed atlas of the response to a single bout of exercise at different times, highlighting the influence of exercise timing on tissue changes and exerkine secretion. source

      Not checked in the free run.

  • Premisecitation

    Physical inactivity is associated with a higher risk of severe COVID-19 outcomes.

    “physical inactivity is associated with increased risk of severe COVID-19 outcomes5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Sallis, R. et al. Physical inactivity is associated with a higher risk for severe COVID-19 outcomes: a study in 48 440 adult patients. Br. J. Sports Med. 55, 1099–1105 (2021). source

      Not checked in the free run.

  • Premisecitation

    Accelerometer data indicate that only 5% of US adults obtain more than 30 minutes of moderate-intensity physical activity per day.

    “only 5% of US adults having more than 30 min of moderate intensity physical activity per day10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Troiano, R. P. et al. Physical activity in the United States measured by accelerometer. Med. Sci. Sports Exerc. 40, 181–188 (2008). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 16
  • May combine two claims. 70

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

    Premisecitation

    During acute exercise in humans, blood glucose typically remains stable, with the liver releasing glucose for brain and skeletal muscle use.

    “In a human model, the blood concentration of glucose typically remains stable during acute exercise, with the liver releasing glucose for brain and skeletal muscle usage28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Wahren, J., Felig, P., Ahlborg, G. & Jorfeldt, L. Glucose metabolism during leg exercise in man. J. Clin. Invest. 50, 2715–2725 (1971). source

      Not checked in the free run.

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

    Premisecitation

    Physical inactivity is associated with increased mortality and a substantial economic burden.

    “physical inactivity poses a major public health threat, as it is associated with increased mortality2 and a notable economic burden3.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Katzmarzyk, P. T., Church, T. S., Craig, C. L. & Bouchard, C. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med. Sci. Sports Exerc. 41, 998–1005 (2009). source

      Not checked in the free run.

    • cites [3] Ding, D. et al. The economic burden of physical inactivity: a global analysis of major non-communicable diseases. Lancet 388, 1311–1324 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Skeletal muscle constitutes about one third of body mass and has an important role in exercise.

    “skeletal muscle comprises approximately one third of body mass and has an important role in exercise14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Janssen, I., Heymsfield, S. B., Wang, Z. & Ross, R. Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J. Appl. Physiol. 89, 81–88 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exercise is associated with altered humoral factors even at rest, suggesting that exerkine changes can reflect chronic training effects.

    “Chronic exercise is also associated with altered humoral factors, even in the resting state, suggesting that exerkine alterations can reflect the effects of chronic training27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Leuchtmann, A. B., Adak, V., Dilbaz, S. & Handschin, C. The role of the skeletal muscle secretome in mediating endurance and resistance training adaptations. Front. Physiol. 12, 709807 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The acute exerkine response is influenced by exercise type, duration, underlying fitness, fed-fasting status and sample timing after exercise.

    “The acute exerkine response is influenced by the type of exercise, duration of exercise, underlying fitness, fed-fasting status and sample timing after exercise.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Physical activity, exercise and cardiorespiratory fitness help prevent and treat chronic diseases such as cardiovascular disease, obesity, type 2 diabetes, cognitive decline and many cancers, and enhance immune function, healthspan, longevity and resilience.

    “Irrefutable evidence supports the importance of physical activity, exercise and cardiorespiratory fitness in the prevention and treatment of chronic diseases, such as cardiovascular disease, obesity, type 2 diabetes mellitus, cognitive decline and many cancers, while enhancing the immune system, healthspan, longevity and resilience1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Piercy, K. L. et al. The physical activity guidelines for Americans. J. Am. Med. Assoc. 320, 2020–2028 (2018). source

      Not checked in the free run.

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

    Premisecitation

    During exercise, skeletal muscle uses lipid fuel from intramuscular triglycerides and free fatty acids released from white adipose tissue.

    “During exercise, skeletal muscle also uses lipid as fuel, which originates from the triglycerides stored in muscle and free fatty acids (FFAs) released from WAT29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Horowitz, J. F. & Klein, S. Lipid metabolism during endurance exercise. Am. J. Clin. Nutr. 72, 558s–563s (2000). source

      Not checked in the free run.

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

    Premisecitation

    IL-6 has been the most extensively studied myokine since its discovery in 2000.

    “Of the myokines, IL-6 has been the most extensively studied since its discovery in 2000 (REF.16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Steensberg, A. et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 529, 237–242 (2000). A key paper demonstrating that IL-6 is secreted by contracting muscle, identifying IL-6 as the first ‘myokine’. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In high-intensity interval training, higher exercise intensity corresponds with higher plasma IL-6, while IL-10 remains unchanged from pre-exercise levels.

    “the exerkine response to high-intensity interval training depends on exercise intensity; higher exercise intensity corresponds with higher plasma levels of IL-6, while IL-10 levels remain unchanged compared with the levels before exercise6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Cullen, T., Thomas, A. W., Webb, R. & Hughes, M. G. Interleukin-6 and associated cytokine responses to an acute bout of high-intensity interval exercise: the effect of exercise intensity and volume. Appl. Physiol. Nutr. Metab. 41, 803–808 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After a marathon, plasma IL-6, IL-1RA, IL-10 and TNF are higher than baseline immediately after exercise, peak 1-2 hours after exercise and remain elevated for about 4 hours.

    “plasma levels of several cytokines (IL-6, IL-1RA, IL-10 and tumour necrosis factor (TNF)) were higher than baseline levels when collected immediately after exercise, peaking 1–2 h after exercise and remaining elevated for ~4 h after exercise30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Ostrowski, K., Rohde, T., Asp, S., Schjerling, P. & Pedersen, B. K. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J. Physiol. 515, 287–291 (1999). One of the earliest papers to examine the effect of acute strenuous exercise, marathon running, on plasma concentrations of pro-inflammatory and anti-inflammatory cytokines. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Identifying an exerkine or panel that captures exercise benefits could help improve health in people unable to exercise, such as those with ageing-associated exercise intolerance.

    “Identification of an exerkine or a panel of exerkines, which capture the benefits of exercise, would have potential implications for improving the health of those unable to exercise, such as those with ageing-associated exercise intolerance.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Extracellular vesicles are membranous structures released from almost all cell types with cell-specific profiles, ranging in size from 150 to 1,000 nm and carrying proteins, nucleic acids and lipids.

    “Extracellular vesicles are membranous structures that are released from almost all cell types, with cell-specific profiles. They vary in size, ranging from 150 nm to 1,000 nm, and carry an assortment of material, including proteins, nucleic acids and lipids18,34.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Vechetti, I. J. Jr, Valentino, T., Mobley, C. B. & McCarthy, J. J. The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise. J. Physiol. 599, 845–861 (2021). source

      Not checked in the free run.

    • cites [34] Safdar, A. & Tarnopolsky, M. A. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb. Perspect. Med. 8, a029827 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, chronic exercise training lowers plasma IL-6, but this effect may be partly offset by increased skeletal muscle mRNA expression of IL-6 receptor.

    “in humans, chronic exercise training reduces plasma concentrations of IL-6; however, this effect could be partially mitigated by increased skeletal muscle mRNA expression of IL-6 receptor32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Keller, C. et al. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J. Appl. Physiol. 99, 2075–2079 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise timing relative to circadian rhythms, fed-fasting status and post-exercise dietary composition may influence metabolic outcomes.

    “exercise timing relative to circadian rhythms21, fed-fasting status22 or post-exercise dietary composition23 might influence metabolic outcomes.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Gabriel, B. M. & Zierath, J. R. Circadian rhythms and exercise–re-setting the clock in metabolic disease. Nat. Rev. Endocrinol. 15, 197–206 (2019). source

      Not checked in the free run.

    • cites [22] Parr, E. B., Heilbronn, L. K. & Hawley, J. A. A time to eat and a time to exercise. Exerc. Sport. Sci. Rev. 48, 4–10 (2020). source

      Not checked in the free run.

    • cites [23] van Loon, L. J. et al. Influence of prolonged endurance cycling and recovery diet on intramuscular triglyceride content in trained males. Am. J. Physiol. Endocrinol. Metab. 285, E804–E811 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exercise responses typically focus on long-term metabolic adaptations and decreased inflammation.

    “chronic exercise exposure is associated with responses focused on long-term metabolic adaptations and decreased inflammation27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Leuchtmann, A. B., Adak, V., Dilbaz, S. & Handschin, C. The role of the skeletal muscle secretome in mediating endurance and resistance training adaptations. Front. Physiol. 12, 709807 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exerkines include a broad range of signalling moieties such as cytokines, nucleic acids, lipids and metabolites, often carried by cell-specific extracellular vesicles.

    “Exerkines are increasingly recognized to include a broad range of signalling moieties, including cytokines, nucleic acids (microRNA17, mRNA and mitochondrial DNA), lipids and metabolites, which are frequently driven by cell-specific extracellular vesicle secretion18.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Baggish, A. L. et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J. Physiol. 589, 3983–3994 (2011). source

      Not checked in the free run.

    • cites [18] Vechetti, I. J. Jr, Valentino, T., Mobley, C. B. & McCarthy, J. J. The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise. J. Physiol. 599, 845–861 (2021). source

      Not checked in the free run.

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

    Premisenone given

    Classic exerkines released during acute exercise in human and animal models include IL-6, IL-8, IL-1RA and IL-10.

    “The classic exerkines released during acute exercise, as found in human and animal models, include IL-6, IL-8, IL-1 receptor antagonist (IL-1RA) and IL-10.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Acute exercise responses typically focus on maintaining metabolic homeostasis, with acute inflammation balanced by anti-inflammatory mediators and shifts in fuel utilization.

    “Typically, acute exercise exposure is associated with responses focused on the maintenance of metabolic homeostasis, with acute inflammation balanced by anti-inflammatory mediators30 and accommodating shifts in fuel utilization.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Ostrowski, K., Rohde, T., Asp, S., Schjerling, P. & Pedersen, B. K. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J. Physiol. 515, 287–291 (1999). One of the earliest papers to examine the effect of acute strenuous exercise, marathon running, on plasma concentrations of pro-inflammatory and anti-inflammatory cytokines. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trained athletes have lower BAT activity and no difference in WAT browning markers compared with lean sedentary men.

    “Trained athletes have lower BAT activity and no difference in WAT browning markers compared with lean, sedentary men89”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Vosselman, M. J. et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int. J. Obes. 39, 1696–1702 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic mice overexpressing muscle PGC1α have higher circulating irisin and increased WAT browning than controls.

    “Transgenic mice that overexpress muscle peroxisome proliferator-activated receptor-γ coactivator 1-α (PGClα) have higher circulating levels of irisin and increased WAT browning than control mice84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012). The first paper to describe irisin, a PGC1α-dependent myokine, that drives ‘browning’ of WAT in an animal model; the extent to which these results might apply to humans remains under investigation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    12,13-diHOME is secreted from brown adipose tissue and increases skeletal muscle oxidative capacity.

    “12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which is secreted from BAT and increases skeletal muscle oxidative capacity91.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1357–1357 (2018). This paper demonstrated that levels of a lipokine produced from brown adipose tissue increase with acute and chronic training to affect white adipose tissue lipolysis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse model, irisin is cleaved from fibronectin type III domain containing 5 in muscle and secreted, inducing WAT browning to increase energy expenditure and reduce obesity.

    “In a mouse model, fibronectin type III domain containing 5 is cleaved in the muscle cell and secreted as irisin, which induces WAT browning to increase energy expenditure and consequently reduce obesity84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012). The first paper to describe irisin, a PGC1α-dependent myokine, that drives ‘browning’ of WAT in an animal model; the extent to which these results might apply to humans remains under investigation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute exercise in humans generally increases plasma irisin, but the effect of chronic exercise training remains highly variable.

    “Although acute exercise in humans generally increases plasma levels of irisin87, the effect of chronic exercise training remains highly variable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Fox, J. et al. Effect of an acute exercise bout on immediate post-exercise irisin concentration in adults: a meta-analysis. Scand. J. Med. Sci. Sports 28, 16–28 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In myonectin knockout mice, WAT lipolysis is unaffected, but dietary lipid clearance is impaired versus wild-type, leading to increased WAT mass and decreased liver steatosis.

    “in myonectin knockout mice, WAT lipolysis is unaffected; however, dietary lipid clearance is impaired compared with lipid clearance in wild-type mice, resulting in increased WAT mass and decreased liver steatosis82.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Little, H. C. et al. Myonectin deletion promotes adipose fat storage and reduces liver steatosis. FASEB J. 33, 8666–8687 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 2021 optimized size-exclusion chromatography method for proteomic analysis of plasma-derived extracellular vesicles from platelet-poor plasma has greater precision than conventional techniques and shows a distinct exosome protein cargo profile after acute exercise in humans.

    “A 2021 paper presented an optimized size-exclusion chromatography method for proteomic analysis of plasma-derived extracellular vesicles from platelet-poor plasma; this technique has greater precision than conventional extracellular vesicle techniques and demonstrates a distinct exosome protein cargo profile after acute exercise in humans37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Vanderboom, P. M. et al. A size-exclusion-based approach for purifying extracellular vesicles from human plasma. Cell Rep. Methods 1, 100055 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interplay between the endothelium and established exerkines such as nitric oxide and VEGF influences vascular tone, inflammation, regeneration and thrombosis, and has an important role in cardiovascular and overall resilience.

    “interplay between the endothelium and established exerkines, such as nitric oxide52 and VEGF27, has been shown to influence vascular tone, inflammation, regeneration and thrombosis, and has an important role in cardiovascular and overall resilience67.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Tejero, J., Shiva, S. & Gladwin, M. T. Sources of vascular nitric oxide and reactive oxygen species and their regulation. Physiol. Rev. 99, 311–379 (2019). source

      Not checked in the free run.

    • cites [27] Leuchtmann, A. B., Adak, V., Dilbaz, S. & Handschin, C. The role of the skeletal muscle secretome in mediating endurance and resistance training adaptations. Front. Physiol. 12, 709807 (2021). source

      Not checked in the free run.

    • cites [67] Gao, Y. & Galis, Z. S. Exploring the role of endothelial cell resilience in cardiovascular health and disease. Arterioscler. Thromb. Vasc. Biol. 41, 179–185 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute exercise increases plasma levels of various microRNAs after exercise, and chronic exercise increases various microRNAs in the resting state.

    “acute exercise increases plasma levels of various microRNAs after exercise, and chronic exercise increases various microRNAs in the resting state17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Baggish, A. L. et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J. Physiol. 589, 3983–3994 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BAT transplantation in mice increased plasma 12,13-diHOME and improved cardiac haemodynamics.

    “A 2021 study showed that BAT transplantation in mice increased plasma levels of 12,13-diHOME and improved cardiac haemodynamics93.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Pinckard, K. M. et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 143, 145–159 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise-related paracrine effects occur in the nervous system, adipose tissue, bone, cartilage, extracellular matrix and immune system.

    “Exercise-related paracrine effects are also observed in the nervous system53, adipose tissue42,54–58, bone59–61, cartilage62, extracellular matrix63,64 and the immune system65,66.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Koliatsos, V. E., Clatterbuck, R. E., Winslow, J. W., Cayouette, M. H. & Price, D. L. Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 10, 359–367 (1993). source

      Not checked in the free run.

    • cites [42] Takahashi, H. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 1, 291–303 (2019). This paper demonstrated that TGFβ2 is secreted from adipose tissue in response to exercise and improves glucose tolerance. source

      Not checked in the free run.

    • cites [59] Kitase, Y. et al. β-aminoisobutyric Acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep. 22, 1531–1544 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Physical activity lowers the risk of cardiometabolic disease and mortality.

    “Physical activity reduces the risk of cardiometabolic disease and mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Muscle secretes VEGF, angiopoietin 1 and IL-8 to regulate tissue angiogenesis, modulate blood flow and increase nutrient availability to support tissue growth.

    “muscle secretes vascular endothelial growth factor (VEGF)45,46, angiopoietin 1 (REF.47) and IL-8 (REF.48) to regulate tissue angiogenesis, modulate blood flow and increase nutrient availability to support tissue growth27,49–52”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Jensen, L., Bangsbo, J. & Hellsten, Y. Effect of high intensity training on capillarization and presence of angiogenic factors in human skeletal muscle. J. Physiol. 557, 571–582 (2004). source

      Not checked in the free run.

    • cites [47] Kim, I. et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ. Res. 86, 24–29 (2000). source

      Not checked in the free run.

    • cites [48] Frydelund-Larsen, L. et al. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Exp. Physiol. 92, 233–240 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C2C12 mouse myocytes and a wild-type mouse model, BAIBA treatment attenuated insulin resistance, reduced inflammation and increased fatty acid oxidation through AMPK and AMPK-PPARδ-dependent pathways in skeletal muscle.

    “In another study using C2C12 mouse myocytes and a wild-type mouse model (palmitate or high-fat diet exposure), BAIBA treatment attenuated insulin resistance, reduced inflammation and increased fatty acid oxidation through AMP-activated protein kinase (AMPK) and a AMPK-PPARδ-dependent pathway in skeletal muscle113.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Jung, T. W. et al. BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK–PPARδ-dependent pathway in mice. Diabetologia 58, 2096–2105 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans and animal models, exercise increases muscle mRNA levels of apelin and possibly serum apelin.

    “In both humans and animal models, exercise increases muscle mRNA levels of apelin94 and possibly serum levels of apelin95,96.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [94] Besse-Patin, A. et al. Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int. J. Obes. 38, 707–713 (2014). source

      Not checked in the free run.

    • cites [95] Kwak, S. E. et al. Effects of exercise-induced apelin on muscle function and cognitive function in aged mice. Exp. Gerontol. 127, 110710 (2019). source

      Not checked in the free run.

    • cites [96] Vinel, C. et al. The exerkine apelin reverses age-associated sarcopenia. Nat. Med. 24, 1360–1371 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In wild-type mice, BAIBA treatment reduced insulin resistance and suppressed inflammation.

    “In wild-type mice, BAIBA treatment reduced insulin resistance and suppressed inflammation55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014). Using a mouse model, this paper demonstrated that a myokine, BAIBA, can ‘brown’ WAT to improve glucose homeostasis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans and mouse models, acute and chronic exercise increase liver-secreted follistatin, which has been reported to antagonize myostatin.

    “in both humans97–99 and mouse models100, acute exercise97,100 and chronic exercise98 increase liver-secreted follistatin, which has been reported to antagonize the effects of myostatin99.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [97] Sargeant, J. A. et al. The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men. Appl. Physiol. Nutr. Metab. 43, 482–490 (2018). source

      Not checked in the free run.

    • cites [98] Seo, M. W. et al. Effects of 16 weeks of resistance training on muscle quality and muscle growth factors in older adult women with sarcopenia: a randomized controlled trial. Int. J. Env. Res. Public Health 18, 6762 (2021). source

      Not checked in the free run.

    • cites [99] Domin, R. et al. Effect of various exercise regimens on selected exercise-induced cytokines in healthy people. Int. J. Env. Res. Public Health 18, 1261 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liver-derived exerkines affect glucose and/or lipid metabolism, WAT browning, lipolysis and cellular homeostasis.

    “These exerkines affect glucose and/or lipid metabolism (for example, angiopoietin-like protein 4 in humans and animal models39,79), browning of WAT (FGF21 in a mouse model106), lipolysis (FGF21 in humans and a mouse model77) and the maintenance of cellular homeostasis (heat shock protein 72 in humans107).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Watt, M. J., Miotto, P. M., De Nardo, W. & Montgomery, M. K. The liver as an endocrine organ–linking NAFLD and insulin resistance. Endocr. Rev. 40, 1367–1393 (2019). source

      Not checked in the free run.

    • cites [79] Catoire, M. et al. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise. Proc. Natl Acad. Sci. USA 111, E1043–E1052 (2014). source

      Not checked in the free run.

    • cites [106] Keipert, S. et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 306, E469–E482 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A sustained increase in plasma 12,13-diHOME preserves cardiac function and remodelling and increases cardiac haemodynamics through a direct cardiomyocyte effect.

    “These findings suggest that a sustained increase in plasma levels of 12,13-diHOME preserves cardiac function and remodelling and increases cardiac haemodynamics through a direct effect on the cardiomyocyte.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Pinckard, K. M. et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 143, 145–159 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute exercise in humans does not alter plasma fetuin-A, but chronic exercise might decrease it.

    “Although acute exercise in humans does not alter plasma levels of fetuin-A97, chronic exercise might decrease plasma levels of fetuin-A72,101.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [97] Sargeant, J. A. et al. The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men. Appl. Physiol. Nutr. Metab. 43, 482–490 (2018). source

      Not checked in the free run.

    • cites [72] Keihanian, A., Arazi, H. & Kargarfard, M. Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients. Physiol. Int. 106, 70–80 (2019). source

      Not checked in the free run.

    • cites [101] Malin, S. K., del Rincon, J. P., Huang, H. & Kirwan, J. P. Exercise-induced lowering of fetuin-A may increase hepatic insulin sensitivity. Med. Sci. Sports Exerc. 46, 2085–2090 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased myostatin function enhances skeletal muscle growth and improves whole-body glycaemic control.

    “Decreased function of myostatin enhances skeletal muscle growth and improves whole-body glycaemic control44,99.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member. Nature 387, 83–90 (1997). This is a key paper describing myostatin (GDF8), which inhibits muscle growth. source

      Not checked in the free run.

    • cites [99] Domin, R. et al. Effect of various exercise regimens on selected exercise-induced cytokines in healthy people. Int. J. Env. Res. Public Health 18, 1261 (2021). source

      Not checked in the free run.

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

    Premisecitation

    The liver secretes about 2,500 proteins identified by liquid chromatography and mass spectrometry.

    “with ~2,500 liver-secreted proteins identified using modern liquid chromatography and mass spectroscopy technologies39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Watt, M. J., Miotto, P. M., De Nardo, W. & Montgomery, M. K. The liver as an endocrine organ–linking NAFLD and insulin resistance. Endocr. Rev. 40, 1367–1393 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, circulating BAIBA increases with chronic training and inversely correlates with insulin resistance.

    “In humans, circulating levels of β-aminoisobutyric acid (BAIBA) increased with chronic training55 and inversely correlated with insulin resistance55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014). Using a mouse model, this paper demonstrated that a myokine, BAIBA, can ‘brown’ WAT to improve glucose homeostasis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Limited human data show acute exercise increases plasma and muscle expression of fractalkine (CX3CL1), which favourably regulates glucose-stimulated insulin secretion by enhancing β-cell function.

    “Limited human data show that an acute exercise bout increases plasma and muscle expression levels of fractalkine (encoded by CX3CL1)70, which is a chemokine that favourably regulates glucose-stimulated insulin secretion by enhancing β-cell function114.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Catoire, M., Mensink, M., Kalkhoven, E., Schrauwen, P. & Kersten, S. Identification of human exercise-induced myokines using secretome analysis. Physiol. Genomics 46, 256–267 (2014). source

      Not checked in the free run.

    • cites [114] Lee, Y. S. et al. The fractalkine/CX3CR1 system regulates β cell function and insulin secretion. Cell 153, 413–425 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exercise in humans and animal models alters gut microbiota composition and functional capacity independently of diet; changes may be independent of weight and contingent on exercise intensity, modality and sustainment.

    “Chronic exercise in humans and animal models alters the composition and functional capacity of the gut microbiota, independently of diet; these exercise-dependent changes in the microbiota might be independent of weight while being contingent on exercise intensity, modality and sustainment108.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Mailing, L. J., Allen, J. M., Buford, T. W., Fields, C. J. & Woods, J. A. Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health. Exerc. Sport. Sci. Rev. 47, 75–85 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, both acute and chronic exercise increase circulating follistatin.

    “In humans, both acute exercise97 and chronic exercise98 increase circulating levels of follistatin.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Sargeant, J. A. et al. The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men. Appl. Physiol. Nutr. Metab. 43, 482–490 (2018). source

      Not checked in the free run.

    • cites [98] Seo, M. W. et al. Effects of 16 weeks of resistance training on muscle quality and muscle growth factors in older adult women with sarcopenia: a randomized controlled trial. Int. J. Env. Res. Public Health 18, 6762 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SPARC regulates cell function and tissue remodelling and inhibits proliferation while promoting apoptosis in a mouse colon cancer cell line.

    “this matricellular protein regulates cell function and tissue remodelling, while inhibiting proliferation and promoting apoptosis of a mouse colon cancer cell line132.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, raising IL-6 through exercise or injection boosts GLP-1 production by intestinal L cells and pancreatic α-cells, which enhances glucose-stimulated insulin secretion.

    “In rodents, increasing IL-6 by exercise or by IL-6 injection increases the production of glucagon-like peptide 1 by intestinal L cells and pancreatic α-cells to enhance glucose-stimulated insulin secretion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking IL-13 have reduced running capacity and fail to show certain exercise-training benefits, including improved glucose tolerance and endurance running capacity.

    “Mice lacking IL-13 show reduced running capacity and do not show certain beneficial effects of exercise training, such as improvements in glucose tolerance and endurance running capacity136.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Knudsen, N. H. et al. Interleukin-13 drives metabolic conditioning of muscle to endurance exercise. Science 368, eaat3987 (2020). This paper showed that type 2 innate lymphoid cells (ILC2s) in skeletal muscle secrete IL-13 to affect the metabolic adaptation to exercise training. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute exercise creates a distinct exerkine environment that persists for several hours after exercise stops, providing a window for immune stimulation.

    “Acute exercise creates a unique exerkine milieu that lasts several hours after exercise cessation, which provides a temporal window for immune function stimulation31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Contrepois, K. et al. Molecular choreography of acute exercise. Cell 181, 1112–1130.e16 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The immune effects of chronic exercise may depend on intensity, with moderate exercise enhancing immunity and strenuous exercise possibly impairing it.

    “The effects of chronic exercise on the immune system might depend on intensity, with immune enhancement by moderate exercise and possible impairment by strenuous exercise124.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Pedersen, B. K. & Toft, A. D. Effects of exercise on lymphocytes and cytokines. Br. J. Sports Med. 34, 246–251 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, infusing IL-6 slows gastric emptying and reduces glucose levels after a meal.

    “In humans, IL-6 infusion delays gastric emptying and lowers postprandial glucose levels118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Lang Lehrskov, L. et al. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 27, 1201–1211.e3 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivating hepatic follistatin in a mouse model improved WAT sensitivity and reduced hepatic glucose production.

    “inactivating hepatic follistatin in a mouse model improved WAT sensitivity and reduced hepatic glucose production116.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Tao, R. et al. Inactivating hepatic follistatin alleviates hyperglycemia. Nat. Med. 24, 1058–1069 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 12 prospective cohorts using self-reported physical activity found that higher activity levels are associated with lower risk of incident cancer across multiple cancer types, with many associations persisting after BMI adjustment.

    “A meta-analysis pooled data from 12 prospective cohorts with self-reported physical activity and found that increased physical activity levels are associated with decreased risk of incident cancer across multiple types; many of these associations remained even after adjusting for BMI129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816–825 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, irisin prevented excessive lipogenesis of mouse islets under glucolipotoxic conditions, improving insulin secretion, inhibiting apoptosis and restoring β-cell function-related gene expression.

    “In vitro, irisin prevented excessive lipogenesis of mouse islets under glucolipotoxic conditions, resulting in improved insulin secretion, inhibition of apoptosis and restored β-cell function-related gene expression117.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Zhang, D., Xie, T. & Leung, P. S. Irisin ameliorates glucolipotoxicity-associated β-cell dysfunction and apoptosis via AMPK signaling and anti-inflammatory actions. Cell Physiol. Biochem. 51, 924–937 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During acute exercise, muscle-secreted exerkines such as fractalkine mobilize immune cells to enhance regeneration in humans, and METRNL increases beige adipose tissue thermogenesis in an animal model.

    “During acute exercise, immune cells are mobilized by muscle secretion of exerkines such as fractalkine to enhance regeneration (in humans)133 or meteorin-like (METRNL) to increase beige adipose tissue thermogenesis (animal model)134.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Strömberg, A. et al. CX3CL1–a macrophage chemoattractant induced by a single bout of exercise in human skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R297–R304 (2016). source

      Not checked in the free run.

    • cites [134] Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy humans, a single exercise bout or an IL-6 infusion reduced the TNF increase caused by lipopolysaccharide infusion.

    “In healthy humans, one bout of exercise or an IL-6 infusion blunted the increase in circulating levels of TNF induced by infusion of lipopolysaccharide128.”
    • Also stated in: § The immune system · plain
      “As previously noted, one bout of exercise or an IL-6 infusion in humans blunts the increase in circulating levels of TNF that are induced by lipopolysaccharide infusion128.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Starkie, R., Ostrowski, S. R., Jauffred, S., Febbraio, M. & Pedersen, B. K. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-α production in humans. FASEB J. 17, 884–886 (2003). An important paper demonstrating that increasing IL-6 either by exercise or by infusion blunts the inflammatory effect of TNF. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy humans, IL-6 infusion at levels comparable to strenuous exercise improves insulin-stimulated glucose uptake without changing whole-body lipolysis or lipid oxidation.

    “In healthy humans, IL-6 infusion to levels similar to those seen with strenuous exercise enhances insulin-stimulated glucose-uptake but does not alter whole-body lipolysis or lipid oxidation120.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Carey, A. L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-13-deficient mice show defective muscle fatty acid utilization after acute exercise and fail to increase muscle mitochondrial biogenesis after chronic exercise.

    “As IL-13-deficient mice show defective muscle fatty acid utilization after acute exercise and fail to show increased muscle mitochondrial biogenesis after chronic exercise, the ILC2 to IL-13 axis might have an important role in the metabolic adaptation to exercise training136.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Knudsen, N. H. et al. Interleukin-13 drives metabolic conditioning of muscle to endurance exercise. Science 368, eaat3987 (2020). This paper showed that type 2 innate lymphoid cells (ILC2s) in skeletal muscle secrete IL-13 to affect the metabolic adaptation to exercise training. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, voluntary wheel running increases the number of new hippocampal neurons, enhances morphological maturation such as dendritic branching and spine density, and alters the circuitry of adult-born neurons.

    “In addition, voluntary wheel running in rodents increases the number of new hippocampal neurons, enhances morphological maturation, such as dendritic branching and spine density, and alters the circuitry of adult-born neurons147.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Vivar, C. & van Praag, H. Running changes the brain: the long and the short of it. Physiology 32, 410–424 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence for exercise benefits on cognition remains variable, probably because of lack of randomized controlled trials across the lifespan with standardized exercise interventions and comparable cognitive assessment methods.

    “Of note, evidence for the benefits of exercise on cognition remains variable, probably owing to the lack of randomized controlled trials throughout the lifespan with standardized exercise interventions and comparable methods for cognitive assessment139–142.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [139] Etnier, J. L., Shih, C.-H. & Piepmeier, A. T. in Exercise-Cognition Interaction (ed. McMorris, T.) 29–42 (Academic Press, 2016). source

      Not checked in the free run.

    • cites [140] Voss, M. W. et al. Exercise and hippocampal memory systems. Trends Cogn. Sci. 23, 318–333 (2019). source

      Not checked in the free run.

    • cites [141] Etnier, J. L. et al. The influence of physical fitness and exercise upon cognitive functioning: a meta-analysis. J. Sport. Exerc. Psychol. 19, 249–277 (1997). source

      Not checked in the free run.

    • cites [142] Colcombe, S. & Kramer, A. F. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol. Sci. 14, 125–130 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine to kynurenic acid, a metabolite unable to cross the blood-brain barrier.

    “In both mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine into kynurenic acid, a metabolite that is unable to cross the blood-brain barrier.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Agudelo, L. Z. et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, adiponectin crosses the blood-brain barrier and is associated with increased neurogenesis and reduced depression-like behaviours.

    “In mice, adiponectin was demonstrated to pass through the blood-brain barrier and was associated with increased neurogenesis and reduced depression-like behaviours151.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Yau, S. Y. et al. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc. Natl Acad. Sci. USA 111, 15810–15815 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, chronic exercise upregulates hippocampal BDNF, which is essential for adult hippocampal neurogenesis and neural plasticity.

    “In rodents, chronic exercise upregulates BDNF in the hippocampus, which is essential for adult hippocampal neurogenesis and neural plasticity146.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Liu, P. Z. & Nusslock, R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front. Neurosci. 12, 52 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In older adults aged 55-80 years, an aerobic walking programme increased hippocampal volume and improved memory.

    “In older adults (aged 55–80 years), participation in an aerobic walking programme increased hippocampal volume and improved memory144.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011). This was a randomized controlled trial in older adults that showed that chronic exercise training increases hippocampal size and improves memory function. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myokines appear to have important roles in hippocampal neurogenesis and neurotrophin levels in animal models, and in enhanced cognition and mood in animal models and humans.

    “Myokines seem to have an important role in hippocampal neurogenesis (animal model) and neurotrophin levels (animal model), and enhanced cognition and mood (animal model and humans) (Supplementary Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, increasing intrinsic irisin expression in neurons or increasing plasma irisin elevates hippocampal Bdnf gene expression.

    “For instance, in mice, increasing intrinsic irisin expression in neurons or increasing plasma levels of irisin elevates hippocampal Bdnf gene expression152.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Wrann, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 18, 649–659 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma proteomic analysis identified GPLD1, a novel hepatokine that increases after exercise and correlates with improved cognitive function in aged mice.

    “Upon further investigation, plasma proteomic analysis led to the identification of a novel hepatokine, glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), which increases after exercise and correlates with improved cognitive function in aged mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020). This paper demonstrated that transfer of plasma from exercised aged mice to sedentary aged mice can confer benefits on the ageing brain, including improvements in cognitive function. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, chronic exercise enhances hippocampal synaptic plasticity, adult neurogenesis, neurotrophin levels, and memory function.

    “Chronic exercise in rodents also enhances hippocampal synaptic plasticity, adult neurogenesis and neurotrophin levels, as well as memory function147.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Vivar, C. & van Praag, H. Running changes the brain: the long and the short of it. Physiology 32, 410–424 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of exercise on the brain are most apparent in the hippocampus, which is involved in learning and memory.

    “The effects of exercise on the brain are most apparent in the hippocampus, a part of the brain involved in learning and memory143.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Neylan, T. C. Memory and the medial temporal lobe. J. Neuropsychiatry Clin. Neurosci. 12, 103 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, acute exercise increases plasma adiponectin but decreases cerebrospinal fluid adiponectin.

    “For example, in humans, acute exercise increases plasma levels of adiponectin but decreases cerebrospinal fluid levels of adiponectin154.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Schön, M. et al. Effects of running on adiponectin, insulin and cytokines in cerebrospinal fluid in healthy young individuals. Sci. Rep. 9, 1959 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adiponectin is an adipocyte-secreted protein with neuroprotective effects, as well as insulin-sensitizing, anti-inflammatory and anti-atherogenic effects.

    “Adiponectin is an adipocyte-secreted protein that seems to have neuroprotective effects151, in addition to its insulin-sensitizing, anti-inflammatory and anti-atherogenic effects151,153.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [151] Yau, S. Y. et al. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc. Natl Acad. Sci. USA 111, 15810–15815 (2014). source

      Not checked in the free run.

    • cites [153] Fu, Y. C., Luo, N. L., Klein, R. L. & Garvey, W. T. Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J. Lipid Res. 46, 1369–1379 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma transfer from exercised young mice to sedentary young mice reduces brain inflammation and improves cognitive function.

    “This paper demonstrated that plasma transfer from exercised young mice to sedentary young mice reduces brain inflammation and improves cognitive function”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021). This paper demonstrated that plasma transfer from exercised young mice to sedentary young mice reduces brain inflammation and improves cognitive function, supporting the potential of transferable anti-inflammatory exerkines in improving brain function. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Exerkines have high potential as biomarkers to predict outcomes, facilitate personalized exercise programmes, improve health, reduce disease and promote resilience across the lifespan.

    “In summary, exerkines are a highly promising direction for future research initiatives, with high potential as biomarkers to predict outcomes, facilitate personalized exercise programmes to improve health, reduce disease and promote resilience across the lifespan.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Initial exerkine research focused on skeletal muscle, but contemporary research is expanding to non-skeletal muscle sources and targets.

    “Much of the initial exerkine research has been focused on skeletal muscle; however, contemporary research is now rapidly expanding to include non-skeletal muscle-based sources and targets for exerkines that contribute to maintaining and restoring health.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Nitric oxide has a vasodilatory role.

    “This paper described the vasodilatory role of nitric oxide.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Palmer, R. M. J., Ferrige, A. G. & Moncada, S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526 (1987). This paper described the vasodilatory role of nitric oxide. source

      Not checked in the free run.

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

    Premisecitation

    Irisin is a PGC1α-dependent myokine that drives browning of white adipose tissue in an animal model.

    “The first paper to describe irisin, a PGC1α-dependent myokine, that drives ‘browning’ of WAT in an animal model”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012). The first paper to describe irisin, a PGC1α-dependent myokine, that drives ‘browning’ of WAT in an animal model; the extent to which these results might apply to humans remains under investigation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exercise training increases hippocampal size and improves memory function in older adults, as shown in a randomized controlled trial.

    “This was a randomized controlled trial in older adults that showed that chronic exercise training increases hippocampal size and improves memory function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011). This was a randomized controlled trial in older adults that showed that chronic exercise training increases hippocampal size and improves memory function. source

      Not checked in the free run.

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

    Interpretationnone given

    Exerkines are increasingly recognized as critical mediators of exercise-related changes and health benefits, particularly in inter-organ and systemic communication and coordination.

    “Exerkines are increasingly recognized as critical mediators of exercise-related changes and health benefits, particularly in their role in inter-organ and systemic communication and coordination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Levels of a lipokine produced from brown adipose tissue increase with acute and chronic training and affect white adipose tissue lipolysis.

    “This paper demonstrated that levels of a lipokine produced from brown adipose tissue increase with acute and chronic training to affect white adipose tissue lipolysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1357–1357 (2018). This paper demonstrated that levels of a lipokine produced from brown adipose tissue increase with acute and chronic training to affect white adipose tissue lipolysis. source

      Not checked in the free run.

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

    Interpretationnone given

    Understanding of mechanisms driving exercise benefits and variability in these benefits remains rudimentary.

    “Although exercise exerts many beneficial effects across multiple organ systems, our understanding of the mechanisms driving the benefits of exercise and the variability in these benefits remains rudimentary.”
    Quote in the paperNot a substantial claim
79 of 79

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?

  • An elevated blood lactate concentration, whether caused by exercise or lactate infusion, could cause several beneficial or detrimental changes in the motor cortex and hippocampus, suggesting that lactate is an important 'stress' or 'exerkine' for functional brain plasticity.

    “An elevated blood lactate concentration, whether caused by exercise or lactate infusion, could cause several beneficial or detrimental changes in the motor cortex and hippocampus, suggesting that lactate is an important ‘stress’ or ‘exerkine’ for functional brain plasticity [18–20].”

    From High-intensity interval training or lactate administration combined with aerobic training enhances visceral fat loss while promoting VMH neuroplasticity in female rats (2024) · cites this paper as [20]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Contracting skeletal muscle produces many molecules that can enhance the cardiovascular system, such as angiopoietin 1, fractalkine, fibroblast growth factor, IL8, musclin, myonectin, IL6, and VEGF, most of which are generally increased mainly with acute exercise.

    “Contracting skeletal muscle produces many molecules that can enhance the cardiovascular system, such as angiopoietin 1, fractalkine, fibroblast growth factor, IL8, musclin, myonectin, or the abovementioned IL6 and VEGF, among others, most of which are generally increased mainly with acute exercise.169,172”

    From Exercise benefits in cardiovascular diseases: From mechanisms to clinical implementation (2023) · cites this paper as [172]

  • Other exerkine-induced effects include improved lipolysis, thermogenesis, and glucose metabolism.

    “Other exerkine-induced effects include improved lipolysis, thermogenesis, and glucose metabolism.169,172”

    From Exercise benefits in cardiovascular diseases: From mechanisms to clinical implementation (2023) · cites this paper as [172]

  • The effect of IL6 on metabolism and inflammation remains context-dependent.

    “As a pleiotropic factor, the effect of IL6 on metabolism and inflammation remains context-dependent.172”

    From Exercise benefits in cardiovascular diseases: From mechanisms to clinical implementation (2023) · cites this paper as [172]

  • The benefits of exercise on cardiovascular health go beyond 'traditional' CVD risk factors, partly owing to the release of exercise-derived factors or exerkines.

    “The benefits of exercise on cardiovascular health go beyond 'traditional' CVD risk factors, partly owing to the release of exercise-derived factors or exerkines (Figure 4).”

    From Exercise benefits in cardiovascular diseases: From mechanisms to clinical implementation (2023) · cites this paper as [172]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. National Heart, Lung, and Blood Institute. NHLBI and NIDDK Workshop: exerkines in health, resilience, and diseases executive summary, https://www.nhlbi.nih.gov/events/2020/nhlbi-and-niddk-workshop-exerkines-health-resilience-and-diseases-executive-summary (2020).

Cited by

Sorted by citations

Related

Authors
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., Lanza, I. R., Lavie, C. J., Lee, C.-H., Lucia, A., Moro, C., Pandey, A., Robbins, J. M., Stanford, K. I., Thackray, A. E., Villeda, S., Watt, M. J., Xia, A., Zierath, J. R., Goodpaster, B. H., & Snyder, M. P.
Affiliations
  • University of Minnesota (US)
  • Beth Israel Deaconess Medical Center (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Copenhagen (DK)
  • Ball State University (US)
  • Monash University (AU)
  • National Institutes of Health (US)
  • University of Michigan (US)
  • Mayo Clinic (US)
  • The University of Queensland (AU)
  • Harvard University (US)
  • The University of Texas Southwestern Medical Center (US)
  • The Ohio State University (US)
  • Loughborough University (GB)
  • University of California, San Francisco (US)
  • The University of Melbourne (AU)
  • AdventHealth Orlando (US)
  • Stanford Medicine (US)
Corresponding author
  • Chow, Lisa S.
  • Goodpaster, Bret H.
  • Snyder, Michael P.
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2022-03-18
Volume
18
Issue
5
Pages
273-289
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/s41574-022-00641-2
PMC
PMC9554896
OpenAlex
W4220828826
Semantic Scholar
1ee97f05bbd80028fbc1206e7828f9e358853c82
Cited by
927
References
204
Citations by year
2026: 207 · 2025: 249 · 2024: 223 · 2023: 169 · 2022: 76 · 2020: 1 · 2014: 1 · 2012: 1
FWCI
21.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Health and Human Services
  • Gilead Sciences
  • University of Minnesota
  • National Institute for Health and Care Research
  • Ministerio de Economía y Competitividad (PI18/00139)
  • Novo Nordisk (NNF18CC0034900)
  • Vetenskapsrådet (2015-00165)
  • Centrum för idrottsforskning (P2018-0097)
  • TrygFonden
  • Novo Nordisk Fonden (NNF17OC0030088, NNF 18 CC0034900)
  • Novo Nordisk Foundation Center for Basic Metabolic Research (NNF 18 CC0034900)
  • Région Occitanie Pyrénées-Méditerranée
  • National Institutes of Health (AG060542)
  • NIHR Leicester Biomedical Research Centre
  • National Institute on Aging (R01AG060542, R03AG067960)
  • National Heart, Lung, and Blood Institute (K23HL150327, R01HL138738, R01HL142879, R01HL165786)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098203, U54DK102556, U24DK112348, P30DK020572, P30DK040561)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (U01AR071133)
Topics
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
exerkines, physical activity, myokines, cardiokines, hepatokines, adipokines, brown adipose tissue, skeletal muscle, interleukin-6, paracrine signaling, hormone signaling, autocrine signaling, healthspan, healthy aging, cardiovascular disease, type 2 diabetes, obesity, resilience
MeSH terms
Diabetes Mellitus, Type 2, Humans, Obesity, Exercise, Muscle, Skeletal, Adipokines

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