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

The DOI matches its Crossref record; 240 of the 249 references it cites were found in a registry or an index; none of the 156 sources its claims cite is checked for support yet.

Muscle–Organ Crosstalk: The Emerging Roles of Myokines

Open access

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.

Overview

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.

Verification

Claims the paper makes

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

Show all 67 claims

  • It may state two separate claims as one. 36
  • Probably not a substantial claim. 3
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

Citations

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Metadata

Authors
Severinsen, M. C. K., & Pedersen, B. K.
Affiliations
University of Copenhagen (DK)
Corresponding author
Pedersen, Bente Klarlund
Venue
Endocrine Reviews
Published
2020-05-11
Volume
41
Issue
4
Pages
594-609
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
OpenAlex
W3024249113
Cited by
1,226
References
249
Citations by year
2026: 280 · 2025: 274 · 2024: 235 · 2023: 191 · 2022: 138 · 2021: 92 · 2020: 15
FWCI
13.32
Type
journal article
Language
en
Open access
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 › Physiology (medical) › Exercise and Physiological Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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

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