Exerkines and IL-6 as an Energy Allocator

Table of Contents

1. Defining Exerkines
2. IL-6 as an Energy Allocator in Muscle Tissue
3. The Three-Phase Cytokine Response to Exercise
4. Multifunctionality of IL-6 – Pro- and Anti-Inflammatory Identity
5. Myokine Responses in Acute Endurance Exercise – Sex and Age Effects
6. Clinical Implications and Outlook

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1 Defining Exerkines

Definition

Exerkines encompass a broad variety of signalling moieties that are released in response to acute and/or chronic exercise and that exert their effects through endocrine, paracrine and/or autocrine pathways [1].

The term exerkine is intentionally broader than myokine — it captures every secreted molecule whose release is causally tied to exercise, regardless of the originating tissue.

Source Tissues

Source tissue	Representative exerkines
Skeletal muscle	IL-6, IL-15, irisin, myostatin (suppressed), BDNF, FGF21
Adipose tissue	Adiponectin, leptin, FGF21
Liver	Hepatokines: FGF21, GDF15, ANGPTL4, follistatin
Bone	Osteocalcin (decarboxylated form)
Brain	BDNF, irisin (CNS effects)
Cardiac muscle	ANP, BNP, FGF21
Immune cells	Soluble cytokines, extracellular vesicles

Table 1. Major source tissues and representative exerkines (selected examples) [1, 2].

Communication Modes

Exerkines act through three distinct distance scales [1]:

• Autocrine — feedback on the secreting cell itself (e.g., muscle-derived IL-6 acting on the muscle fibre).
• Paracrine — local action on neighbouring cells (e.g., on resident macrophages within the muscle).
• Endocrine — systemic action on distant organs (liver, brain, adipose tissue, gut).

Many exerkines act on multiple scales depending on the dose, the duration of exposure, and the receptor density of the target tissue.

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2 IL-6 as an Energy Allocator in Muscle Tissue

A Three-Stage Model

The Kistner–Pedersen–Lieberman model [3] reframes muscle-derived IL-6 as an energy allocator that integrates a contracting muscle’s metabolic state with whole-body substrate flux. The model identifies three sequential roles:

1. Energy sensing — IL-6 is released as a signal that intramuscular energy stores are depleted, particularly in low-glycogen states.
2. Energy liberation — circulating IL-6 upregulates lipolysis and gluconeogenesis, mobilising fuel from adipose tissue and the liver.
3. Energy allocation — IL-6 increases energy uptake into target tissues through enhanced insulin receptor sensitivity, GLUT4 expression and short-chain fatty acid transporter expression.

Phase	Tissue role	Effector mechanism
Sensing	Skeletal muscle (myocyte)	Glycogen depletion → IL-6 transcription / release
Liberation	Adipose tissue, liver	↑ lipolysis, ↑ gluconeogenesis
Allocation	Skeletal muscle, gut	↑ insulin sensitivity, ↑ GLUT4, ↑ SCFA transporters

Table 2. IL-6 as an energy allocator — the three-stage model of Kistner, Pedersen & Lieberman (2022) [3].

Why “Allocator” Rather Than “Pro-Inflammatory Cytokine”

The dominant pre-2008 framing treated IL-6 as a pro-inflammatory mediator analogous to IL-1β and TNF-α. The myokine framework — initiated by Pedersen and Febbraio [4] and matured by Kistner et al. [3] — shows that exercise-induced IL-6 has a distinct kinetic, source, and downstream signalling profile from infection-induced IL-6:

• exercise-induced IL-6 is released by contracting myocytes in the absence of TNF-α activation;
• it operates predominantly through classical (membrane-bound) IL-6R signalling rather than trans-signalling;
• it stimulates AMPK and PI3K-Akt pathways relevant to energy metabolism rather than NF-κB driven inflammatory cascades.

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3 The Three-Phase Cytokine Response to Exercise

Acute Exercise

Acute dynamic exercise — particularly endurance exercise of sufficient duration and intensity — produces a stereotyped cytokine cascade [4, 5]:

1. Early IL-6 rise (during and immediately after exercise): up to 100-fold over baseline in prolonged exercise, dominated by muscle-derived IL-6.
2. Anti-inflammatory follow-on: IL-10 and IL-1Ra rise after IL-6, dampening downstream inflammatory tone.
3. Late effects on metabolism: increased lipolysis, gluconeogenesis and insulin sensitivity for hours after exercise.

Crucially, exercise-induced IL-6 release is largely independent of TNF-α — distinguishing it from the IL-6 surge of infection or sepsis (see Lecture 8).

Chronic Exercise

Regularly performed exercise lowers basal levels of pro-inflammatory cytokines (TNF-α, IL-6, CRP) [5]. The mechanisms include:

• repeated acute IL-6 / IL-10 cycles training a more anti-inflammatory baseline,
• reduction of visceral adiposity (a primary source of chronic low-grade inflammation),
• improved mitochondrial function and reduced reactive oxygen species (ROS) leakage,
• shift in immune cell phenotypes towards regulatory and anti-inflammatory profiles.

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4 Multifunctionality of IL-6 – Pro- and Anti-Inflammatory Identity

Extensive research has shown that IL-6 is a multifunctional molecule that is both pro-inflammatory and anti-inflammatory, depending on the context [3, 4, 5].

Pleiotropic Roles of IL-6

• Acute-phase response. IL-6 drives hepatic CRP and SAA synthesis during infection and injury.
• Haematopoiesis. IL-6 supports megakaryocyte maturation and platelet production.
• Bone and skeletal muscle homeostasis. IL-6 contributes to bone remodelling and muscle mass regulation.
• Central nervous system activity. IL-6 modulates fever, fatigue and HPA-axis signalling.
• Metabolism. Exercise-derived IL-6 sensitises tissues to insulin and mobilises fuel.

Energetic-Stress Signal

Early myokine work established that IL-6 is secreted directly from myocytes and is highly sensitive to physical activity stimulus, particularly when intramuscular glycogen is reduced [3, 4]. In this sense, IL-6 functions as an energy-sensor cytokine: a single molecule whose function depends on the metabolic background in which it is released.

Practical insight. Whether IL-6 is “harmful” or “beneficial” is not a property of the molecule but of the context. The same numerical IL-6 value can reflect productive adaptation (post-exercise myokine signalling) or pathological inflammation (sepsis, chronic disease) — see Lecture 8.

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5 Myokine Responses in Acute Endurance Exercise – Sex and Age Effects

The Ringleb et al. (2026) Study

Ringleb, Fabritius, Godde, Puta, Bloch and Javelle [6] characterised circulating myokine responses to a standardised acute endurance bout and their role in immunomodulation during ageing. The study emphasises four points:

1. Immunosenescence and inflammaging make exercise therapy in older adults particularly important, but the biological signal is heterogeneous.
2. Acute moderate and intense exercise modulates peripheral immune responses in aging — myokine pulses, immune-cell trafficking, and cytokine balance shift in measurable ways.
3. Extracellular vesicle (EV) release and immune activation are part of the exerkine response, with distinct profiles between sexes.
4. Further studies are needed to clarify sex-specific immune responses to exercise so that future interventions can be personalised by sex and age.

Why Sex-Specific Profiles Matter

Sex hormones modulate both immune-cell phenotypes and adipose-tissue exerkine output. Pre-clinical and human work shows:

• differing baseline cytokine tone (e.g., higher IL-6 reactivity in some studies of older women),
• differing kinetics of myokine release and clearance,
• differing extracellular-vesicle cargoes after identical exercise stimuli.

Personalised exercise prescription in older adults therefore needs to consider not only fitness baseline and comorbidity but biological sex as a modifying variable.

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6 Clinical Implications and Outlook

From Mechanism to Prescription

The exerkine framework anchors most of the rest of this lecture series:

• Lecture 4–5 (prediabetes, metabolic syndrome): IL-6, FGF21 and adipokine balance underlie insulin sensitivity.
• Lecture 6 (exercise snacks): short bouts produce measurable acute exerkine pulses without requiring prolonged sessions.
• Lecture 8 (acute and chronic inflammation): the exerkine cascade explains the biphasic immune response to exercise.
• Lecture 9–10 (MAFLD, IBD): tissue-specific exerkines (hepatokines, gut-derived signals) mediate disease-modifying effects.
• Lecture 12 (inter-organ communication): synthesises the exerkine framework into a system view.

Open Questions

• Which exerkines mediate the cross-tissue effects most relevant to chronic disease prevention?
• How does habitual exercise reshape baseline exerkine expression independent of acute pulses?
• Are extracellular vesicle cargos a viable clinical biomarker class for “exercise dose”?

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References

• [1] Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, Febbraio MA, Allen DB, Tweden K, Stein RI, Ravussin E, Goodpaster BH, Snyder MP. Exerkines in health, resilience and disease. Nature Reviews Endocrinology. 2022;18:273–289. doi:10.1038/s41574-022-00641-2.
• [2] Pedersen BK. The physiology of optimizing health with a focus on exercise as medicine. Annual Review of Physiology. 2019;81:607–627. doi:10.1146/annurev-physiol-020518-114339.
• [3] Kistner TM, Pedersen BK, Lieberman DE. Interleukin 6 as an energy allocator in muscle tissue. Nature Metabolism. 2022;4(2):170–179. doi:10.1038/s42255-022-00538-4.
• [4] Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiological Reviews. 2008;88(4):1379–1406. doi:10.1152/physrev.90100.2007.
• [5] Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature Reviews Immunology. 2011;11(9):607–615. doi:10.1038/nri3041.
• [6] Ringleb M, Fabritius F, Godde J, Puta C, Bloch W, Javelle F. Circulating myokine responses to acute endurance exercise and their role in immunomodulation during ageing. FASEB Journal. 2026;40(4):e71536. doi:10.1096/fj.202504780R. PMID: 41661185.
• [7] Frontiers in Immunology. Exerkines and immune ageing — selected reviews 2025. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1661161/full

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One-Minute-Paper Topics

1. Define exerkine and contrast it with the narrower term myokine.
2. List three exerkine source tissues and one representative molecule for each.
3. Distinguish autocrine, paracrine and endocrine exerkine action with one example of each.
4. Reproduce Table 2: the three-stage IL-6 model — sensing, liberation, allocation. Which downstream pathway does each stage activate?
5. Why does the Kistner–Pedersen–Lieberman model describe IL-6 as an allocator rather than a pro-inflammatory cytokine?
6. Exercise-induced IL-6 release is largely independent of TNF-α. Why does this distinction separate the exercise IL-6 surge from the sepsis IL-6 surge?
7. Describe the kinetics of the three-phase acute cytokine response (IL-6 → IL-10 / IL-1Ra → metabolic effects) over a single 60-minute endurance bout.
8. What does chronic exercise do to basal levels of TNF-α, IL-6 and CRP? Name two mechanisms.
9. List the five pleiotropic roles of IL-6 reproduced in Section 4. Which two are most relevant for exercise prescription in older adults?
10. Glycogen depletion enhances exercise-induced IL-6 release. Design a single experiment that would test this dependency in trained humans.
11. Why is the same IL-6 concentration interpretable as either productive adaptation or pathological inflammation? What contextual variables disambiguate the two?
12. The Ringleb et al. study reports sex-specific extracellular vesicle responses. Name one hormonal candidate that could mediate this difference.
13. Define immunosenescence and inflammaging in one sentence each. Why are they relevant to exercise prescription in older adults?
14. Distinguish classical IL-6 signalling from trans-signalling. Why does this matter for the metabolic vs. inflammatory framing of IL-6?
15. The myokine framework predicts that low-glycogen training amplifies the IL-6 response. What are the practical risks and benefits of “train low, compete high” protocols in elite endurance athletes?
16. Identify two exerkines released by skeletal muscle that have CNS effects. What clinical conditions are they being investigated for?
17. Hepatokines such as FGF21 increase after acute exercise. What metabolic effects does FGF21 produce, and which disease state would it most plausibly modify?
18. Sketch a study design that would test whether circulating extracellular vesicle cargo predicts long-term cardiometabolic outcomes after 6 months of structured training.
19. Why does the lecture argue that future exercise prescription must consider biological sex as a moderator? Give one concrete example from immunology.
20. In a 70-year-old patient with chronic low-grade inflammation, type 2 diabetes and reduced muscle mass, sketch a three-component exercise prescription (mode, intensity, frequency) that maximises the exerkine response while remaining safe.