Interleukin-6 (IL-6) · Tier 1 · Anti-inflammatory
Released by Skeletal muscle.
How it works Muscle contraction; blood levels can rise up to 100-fold. → IL-6 receptor with gp130 (membrane-bound or soluble). → JAK/STAT, MAPK and PI3K. → A short spike is anti-inflammatory; chronically high IL-6 drives inflammation.
- Blood and immune cells: Classical signaling through membrane-bound receptors is anti-inflammatory; trans-signaling through soluble receptors drives chronic inflammation.
- Liver: Breaks down liver glycogen to release glucose during exercise.
- Fat (adipose tissue): Stimulates fat breakdown (lipolysis).
Insulin-like Growth Factor 1 (IGF-1) · Tier 1 · Musculoskeletal
Released by Liver, Skeletal muscle.
How it works Growth hormone (liver); exercise raises local production in muscle. → IGF-1 receptor. → MAPK and PI3K. → Growth, protein synthesis and cell survival.
- Skeletal muscle: Drives anabolism and muscle remodeling; exercise raises local production.
- Bone: Supports bone remodeling.
- Brain and spinal cord: Emerging applications in autism spectrum disorder and Alzheimer's disease.
Vascular Endothelial Growth Factor (VEGF) · Tier 1 · Oncology
Released by Skeletal muscle.
How it works Acute exercise activates AMPK, raising VEGF mRNA and protein in muscle. → VEGF receptors (VEGFR1/2). → PI3K/Akt and MAPK. → Angiogenesis.
- Blood vessels: Endothelial survival, proliferation and migration: new capillaries.
- Heart: Intracoronary VEGF-A gene transfer improves myocardial perfusion in ischemic heart disease.
- Tumours: Tumours co-opt angiogenesis; anti-VEGF drugs block it.
- Eye: Anti-VEGF therapy treats pathological angiogenesis in the eye.
β-Hydroxybutyrate (BHB) · Tier 1 · Cardiovascular
Released by Liver.
How it works Made by the liver; rises during recovery after exercise. → GPR109A, a cell-surface receptor. → Inside cells, it inhibits histone deacetylases; it also inhibits the NLRP3 inflammasome. → More myocardial and cerebral blood flow; less inflammation.
- Heart: Raises myocardial blood flow and cardiac output.
- Brain and spinal cord: Crosses the blood–brain barrier; a 14-day trial raised cerebral blood flow by up to 12% and improved cognition.
- Blood and immune cells: Inhibits the NLRP3 inflammasome.
Neuregulin 1 (NRG1) · Tier 2 · Cardiovascular
Released by Heart, Skeletal muscle. Fat releases a related family member, NRG4, after resistance training and HIIT.
How it works Heart and muscle release NRG1; resistance training and HIIT make fat release NRG4. → ErbB/HER receptor tyrosine kinases. → PI3K/Akt, MAPK/ERK and mTOR. → Cardiac repair and function.
- Heart: Improves cardiac function in chronic heart failure.
- Brain and spinal cord: Protects in stroke models even when given 13 h after the event; may preserve synapses in Alzheimer's disease.
Glial Cell Line-Derived Neurotrophic Factor (GDNF) · Tier 2 · Neurological
Released by Skeletal muscle, Brain and spinal cord (spinal cord).
How it works Depends on intensity: low intensity raises it in slow-twitch muscle; high intensity recruits fast-twitch fibres. → RET receptor tyrosine kinase with GFRα1. → Survival of dopaminergic and motor neurons.
- Brain and spinal cord (midbrain): Maintains midbrain dopaminergic neurons.
- Brain and spinal cord (spinal cord): Maintains spinal motor neurons.
Follistatin · Tier 2 · Musculoskeletal
Released by Liver.
How it works Exercise raises the glucagon-to-insulin ratio; plasma levels rise up to sevenfold after prolonged cycling. → Binds activin, myostatin and other TGF-β family members. → Blocks them from reaching their receptors. → Muscle growth.
- Skeletal muscle: Neutralizes myostatin and activin, lifting the brake on muscle growth.
- Pancreas: Maintains β-cell function and improves glycemic control.
- Liver: Antifibrotic in models of liver fibrosis; also antifibrotic in sepsis models.
N-lactoyl-phenylalanine (Lac-Phe) · Tier 2 · Metabolic
Released by Blood and immune cells. Made by cells that express CNDP2, including immune and epithelial cells.
How it works The enzyme CNDP2 joins lactate and phenylalanine; the most strongly induced metabolite in exercising mice, racehorses and humans. → Not identified; it acts on appetite centres in the hypothalamus. → Less food intake; in obese mice, better glucose control and less fat.
- Brain and spinal cord (hypothalamus): Suppresses food intake through central appetite centres.
Growth Differentiation Factor 15 (GDF15) · Tier 2 · Metabolic
Released by Many tissues.
How it works Stress-induced; levels rise during exercise. → GFRAL with RET, in the hindbrain. → Less appetite.
- Brain and spinal cord (hindbrain): Suppresses appetite through GFRAL in the hindbrain.
Brain-Derived Neurotrophic Factor (BDNF) · Tier 2 · Neurological
Released by Brain and spinal cord, Skeletal muscle.
How it works Made in the brain and muscle during activity, and raised by CTSB, GPLD1 and irisin. → TrkB. → PI3K/Akt, MAPK/ERK and PLCγ. → Neuronal survival, synaptic plasticity and mitochondrial biogenesis.
- Brain and spinal cord (hippocampus): Neuronal survival and synaptic plasticity; reduces amyloid-β accumulation and tau phosphorylation in Alzheimer's models.
- Brain and spinal cord (midbrain): Sustains dopaminergic neurons in Parkinson's disease.
- Brain and spinal cord: Promotes remyelination in multiple sclerosis.
- Skeletal muscle: Acts locally in muscle, where it supports mitochondrial biogenesis.
IC7Fc (IL-6/CNTF chimeric cytokine) · Tier 2 · Cardiovascular
Released by Engineered.
How it works Designed in the lab: an IL-6/CNTF chimera fused to an Fc domain. → Membrane-bound receptors only (classical signaling). → Bypasses proinflammatory trans-signaling. → Lower blood lipids and less atherosclerosis in mice.
- Liver: Suppresses lipogenesis, lowering plasma triglycerides and total cholesterol.
- Blood vessels: Shrinks atherosclerotic lesions in mice.
Lactate · Tier 2 · Metabolic
Released by Skeletal muscle.
How it works Contracting muscle, especially during intense exercise. → HCAR1 (GPR81), on the cell surface. → Inside cells, lactate is the substrate for histone lactylation, an epigenetic mark. → A fuel and a signal; it spawns two other exerkines.
- Fat (adipose tissue): Drives the release of TGF-β2.
- Blood and immune cells: Substrate for Lac-Phe.
- Liver: The main precursor for glucose production in the liver.
- Tumours: Histone lactylation may alter how cancer cells behave.
- Brain and spinal cord: Hypertonic sodium lactate infusions have been tested in human studies of traumatic brain injury. (further effect mentioned in the review)
- Heart: Hypertonic sodium lactate infusions have been tested in human studies of heart failure. (further effect mentioned in the review)
Klotho · Tier 2 · Oncology
Released by Kidney, Brain and spinal cord (choroid plexus).
How it works Chronic training raises circulating soluble Klotho (meta-analysis). → Circulating (soluble) Klotho has no single receptor; the membrane form is the co-receptor for FGF23. → Suppresses TGF-β, IGF-1, Wnt and NF-κB. → Anti-tumour and anti-aging effects.
- Tumours: Suppresses TGF-β, IGF-1, Wnt and NF-κB signaling; inhibited tumour growth in animals.
- Kidney: Regulates phosphate and calcium balance as the FGF23 co-receptor.
- Brain and spinal cord: A longevity factor with cognitive benefits; in mice, it raised PF4, which may carry part of this benefit.
Irisin (FNDC5 cleavage product) · Tier 3 · Metabolic
Released by Skeletal muscle.
How it works Contraction switches on PGC-1α; exercise cleaves the muscle protein FNDC5 into irisin. → Integrin αV/β5. → Raises UCP1 in fat cells. → Fat browning, insulin secretion, BDNF in the brain.
- Fat (adipose tissue): Turns energy-storing white fat into heat-producing, brown-like fat.
- Pancreas: Improves insulin secretion.
- Brain and spinal cord: Crosses the blood–brain barrier and raises BDNF.
- Bone: Benefits bone.
- Heart: Benefits the heart.
Follistatin-like 1 (FSTL1) · Tier 3 · Cardiovascular
Released by Skeletal muscle, Heart.
How it works Endurance and resistance training. → DIP2A. → Smad2/3 (angiogenesis); AMPK and BMP-4 (anti-apoptotic). → Smaller infarcts and new coronary vessels.
- Heart: Shrinks infarcts by blocking apoptosis and drives coronary angiogenesis.
- Brain and spinal cord: Limits tissue damage in models of ischemic stroke.
- Lungs: Neutralizing antibodies reduced lung fibrosis.
- Skin: Neutralizing antibodies reduced skin fibrosis.
- Joints and cartilage: Can sometimes drive inflammation in osteoarthritic joints.
ELABELA (ELA) · Tier 3 · Cardiovascular
Released by Kidney.
How it works Spikes with aerobic exercise; secreted mainly by the kidneys. → APJ (apelin receptor). → Akt; SIRT3 and its antioxidant targets. → Lower blood pressure and less cardiac fibrosis.
- Blood vessels: Lowers diastolic blood pressure and promotes angiogenesis.
- Heart: Limits cardiac fibrosis; in diabetic cardiomyopathy it raises SIRT3 and protects microvascular endothelial cells against ferroptosis.
Fractalkine (CX3CL1) · Tier 3 · Anti-inflammatory
Released by Skeletal muscle, Blood vessels, Brain and spinal cord.
How it works Endurance and resistance exercise raise CX3CL1 in muscle. → CX3CR1. → ERK and NF-κB. → Less neuroinflammation; more insulin secretion.
- Brain and spinal cord: Regulates microglial activation, reducing neuroinflammation.
- Pancreas: Restores glycemia by stimulating insulin secretion from β cells.
- Tumours: Recruits antitumour immune cells in colorectal, breast and lung cancers, yet promotes tumour growth in other cancers.
Omentin · Tier 3 · Metabolic
Released by Fat (adipose tissue).
How it works Physical activity raises omentin from visceral fat. → NF-κB inhibition; AMPK/PPARδ; PI3K/AKT/FOXO1. → Less inflammation, endothelial repair and wound healing.
- Blood and immune cells: Blocks NF-κB and reduces IL-6 and TNF-α.
- Heart: Limits myocardial infarct size.
- Blood vessels: Restores endothelial function through AMPK/PPARδ.
- Skin: Promotes diabetic wound healing through PI3K/AKT/FOXO1.
Apelin · Tier 3 · Cardiovascular
Released by Fat (adipose tissue), Many tissues.
How it works Exercise; apelin is also an adipokine. → APJ (apelin receptor). → Protective Gαi pathway; prevents the β-arrestin hypertrophic response to stretch. → Stronger contraction, vasodilation and less hypertrophy.
- Heart: Enhances contractility and mitigates maladaptive hypertrophy.
- Blood vessels: Promotes vasodilation.
Adiponectin · Tier 3 · Metabolic
Released by Fat (adipose tissue).
How it works Exercise increases the expression of its receptors. → AdipoR1 and AdipoR2. → AMPK and PPARα. → Better insulin sensitivity.
- Skeletal muscle: Improves insulin sensitivity by stimulating fatty acid oxidation.
- Liver: Suppresses glucose production by the liver.
- Brain and spinal cord (hippocampus): Crosses the blood–brain barrier and modulates hippocampal neurogenesis.
Decorin · Tier 3 · Musculoskeletal
Released by Skeletal muscle.
How it works Released during resistance exercise. → Binds myostatin and TGF-β; inhibits many receptor tyrosine kinases. → Raises Myod1 and follistatin. → Muscle growth; antifibrotic and anti-tumour effects.
- Skeletal muscle: Binds myostatin and raises Myod1 and follistatin, promoting hypertrophy; antifibrotic: sequesters TGF-β.
- Heart: Improves cardiac function after myocardial infarction; antifibrotic: sequesters TGF-β.
- Tumours: Acts as a pan-receptor tyrosine kinase inhibitor to suppress tumour growth.
- Liver: Antifibrotic: sequesters TGF-β.
- Skin: Antifibrotic: sequesters TGF-β.
Kynurenic Acid (KYNA) · Tier 3 · Neurological
Released by Skeletal muscle.
How it works Muscle PGC-1α raises kynurenine aminotransferases (KATs). → Muscle KATs convert circulating kynurenine, which crosses the blood–brain barrier, into KYNA, which largely cannot. → Less neurotoxic kynurenine reaches the brain.
- Brain and spinal cord: Shields the brain from stress-induced depression by keeping kynurenine out.
Clusterin (CLU; Apolipoprotein J) · Tier 3 · Neurological
Released by Liver, Skeletal muscle.
How it works Identified by transferring plasma from exercised mice; removing it from the plasma abolished the cognitive benefits. → Brain endothelial cells; the review does not name a receptor. → Extracellular chaperone; inhibits the complement cascade. → Less brain inflammation and amyloid-β.
- Brain and spinal cord: Helps clear amyloid-β across the blood–brain barrier and inhibits the complement cascade in brain endothelial cells.
Heat Shock Protein 72 (HSP72) · Tier 3 · Anti-inflammatory
Released by Liver, Skeletal muscle.
How it works Released from muscle and the hepatosplanchnic circulation during exercise. → Misfolded proteins: it is a molecular chaperone that guides protein folding. → Blocks HMGB1 release; suppresses MAPK and NF-κB. → Less inflammation and protein aggregation; cell survival.
- Blood and immune cells: Prevents macrophages from releasing HMGB1, suppressing MAP kinase and NF-κB.
- Heart: Protects cardiac tissue from apoptosis.
- Skeletal muscle: Enhances insulin signaling.
- Brain and spinal cord: An Fv-HSP72 fusion was effective in models of cerebral infarction.
β-Aminoisobutyric Acid (BAIBA) · Tier 3 · Metabolic
Released by Skeletal muscle.
How it works Released by the same PGC-1α signal as irisin. → MRGPRD on bone cells; the receptor in fat and liver is not named. → AMPK and PPARα. → Fat browning, fat burning in the liver, bone cell survival.
- Fat (adipose tissue): Turns white fat brown-like, through a different receptor from irisin.
- Liver: Helps the liver burn fat; reversed liver insulin resistance in diabetic mice.
- Bone: Keeps osteocytes alive.
Myonectin (CTRP15) · Tier 4 · Musculoskeletal
Released by Skeletal muscle.
How it works Exercise raises it. → S1P/cAMP/Akt and AMPK/PGC-1α. → Fatty acid uptake, cardioprotection and less muscle wasting.
- Fat (adipose tissue): Promotes fatty acid uptake by fat cells.
- Liver: Promotes fatty acid uptake by liver cells.
- Heart: Its rise during exercise is necessary for protection against ischemia/reperfusion injury.
- Skeletal muscle: Reduced muscle atrophy and wasting in mouse models.
Lubricin (PRG4) · Tier 4 · Musculoskeletal
Released by Joints and cartilage.
How it works Joint movement and exercise raise its expression. → Cartilage surfaces, as a boundary lubricant; it also antagonizes TLR2 and TLR4. → Mainly physical: boundary lubrication. It also inhibits inflammatory signaling. → Cartilage protection.
- Joints and cartilage: Reduces friction between cartilage surfaces, which prevents chondrocyte death.
- Eye: Recombinant human PRG4 has been effective in dry eye disease.
Platelet Factor 4 (PF4; CXCL4) · Tier 4 · Neurological
Released by Blood and immune cells. Released by platelets.
How it works Platelets degranulate during exercise. → CXCR3. → Hippocampal neurogenesis and better cognition.
- Brain and spinal cord (hippocampus): Crosses the blood–brain barrier and stimulates neurogenesis through CXCR3; restored cognition in aged mice.
Transforming Growth Factor-β2 (TGF-β2) · Tier 4 · Metabolic
Released by Fat (adipose tissue).
How it works Exercise-raised lactate drives its release from fat. → TGF-β receptors. → Smad signaling. → More glucose and fatty acid uptake in muscle.
- Skeletal muscle: Makes muscle take up more glucose and fatty acids and boosts mitochondrial capacity.
Vasoactive Intestinal Peptide (VIP) · Tier 4 · Neurological
Released by Gut, Brain and spinal cord, Blood vessels.
How it works Rises during acute physical activity. → VPAC receptors. → cAMP/PKA and PLC/PKC. → Stronger synaptic transmission and myelin repair.
- Brain and spinal cord (hippocampus): Strengthens synaptic transmission in the hippocampus.
- Brain and spinal cord: Promotes myelin repair.
- Blood vessels: A vasodilator.
- Gut: Loss of VIP after spinal cord injury leads to severe bowel dysfunction.
- Tumours: Acts as an immune checkpoint; VIP antagonists are being developed to boost T cells against cancers such as pancreatic adenocarcinoma.
Carbon Monoxide (CO) · Tier 4 · Anti-inflammatory
Released by Many tissues.
How it works Exercise induces heme oxygenase-1, which produces carbon monoxide. → NLRP3 inflammasome. → Less inflammation; limits ischemia/reperfusion injury in organ transplants.
- Blood and immune cells: Suppresses the NLRP3 inflammasome in macrophages.
- Tumours: Promotes immunogenic cell death in cancer immunotherapy.
Cathepsin B (CTSB) · Tier 4 · Neurological
Released by Skeletal muscle.
How it works Released from muscle during physical activity. → Amyloid precursor protein, which this lysosomal enzyme cleaves. → Upregulates BDNF. → Hippocampal BDNF and less plaque.
- Brain and spinal cord (hippocampus): Crosses the blood–brain barrier and upregulates BDNF in the hippocampus; cleaves amyloid precursor protein, reducing plaque.
Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) · Tier 4 · Neurological
Released by Liver.
How it works Identified by transferring plasma from exercised to sedentary aged mice. → Cleaves the GPI anchors of membrane proteins. → Suppresses the uPAR pathway; releases GAL3BP. → Less amyloid-β production and cognitive benefits in mice.
- Brain and spinal cord: Acts from the periphery: suppresses the uPAR coagulation pathway and releases GAL3BP, which inhibits amyloid-β production in the brain.
Fibroblast Growth Factor 2 (FGF2) · Tier 4 · Oncology
Released by Skeletal muscle.
How it works FGF receptors (FGFRs). → Tissue growth and angiogenesis.
- Blood vessels: Stimulates tissue growth and angiogenesis.
- Tumours: Can promote tumour metastasis.
Selenoprotein P (SeP) · Tier 4 · Oncology
Released by Liver.
How it works Exercise lowers it: an inverse exerkine. → Suppresses insulin receptor autophosphorylation and AKT and AMPK signaling. → When high: insulin and exercise resistance.
- Liver: When high, inhibits insulin signaling, AKT and AMPK, causing insulin resistance.
- Skeletal muscle: Causes insulin resistance and, through reductive stress, atrophy during inactivity.
- Lungs: High levels are implicated in pulmonary hypertension.
- Brain and spinal cord: A possible target to halt neurodegeneration driven by microglial extracellular vesicles.
