Interleukin-6 (IL-6) is a pleiotropic cytokine that functions as both a pro-inflammatory and anti-inflammatory mediator depending on the physiological context. PMID 37841263PMID 35969896 It is considered an exerkine (specifically a myokine) because skeletal muscle produces and releases it during physical exercise. PMID 32563931PMID 18923185
", "biologicalFunction": "IL-6 belongs to the four-helical cytokine family and is secreted by various cell types, including macrophages, T cells, and skeletal muscle. PMID 35969896PMID 32864098 It signals through a membrane-bound IL-6 receptor (IL-6R) that complexes with the signal-transducing glycoprotein 130 (gp130), activating intracellular JAK/STAT, MAPK, and PI3K pathways. PMID 35969896PMID 32864098 IL-6 regulates diverse biological functions including acute-phase responses, B-cell maturation, hematopoiesis, immune system coordination, metabolism, and neural development. PMID 37841263PMID 18923185PMID 33872590
", "exerkineClassification": "The classification of IL-6 as an exerkine is supported by several key findings. During exercise, IL-6 levels can increase up to 100-fold in circulation, with the contracting skeletal muscle identified as the primary source. PMID 18923185PMID 12205025 This discovery led to the recognition of skeletal muscle as an endocrine organ capable of producing \"myokines\"—cytokines secreted by muscle fibers that exert autocrine, paracrine, or endocrine effects. PMID 18923185PMID 21799452 IL-6 appears to function as an energy sensor during exercise, activating hepatic glycogenolysis and adipose tissue lipolysis to meet increased metabolic demands. PMID 24655147PMID 21799452 The magnitude of IL-6 release correlates with exercise intensity, duration, and muscle glycogen depletion. PMID 24655147PMID 12205025 Studies blocking IL-6 during exercise training prevented beneficial adaptations such as reductions in visceral and epicardial fat mass, further supporting its physiological role as an exercise-induced myokine. PMID 32563931
", "therapeuticPotential": "IL-6 represents a unique paradigm in exerkine biology: it is simultaneously the most clinically successful therapeutic target among exercise-induced myokines and a beneficial metabolic regulator during physical activity. This apparent paradox reflects IL-6's context-dependent biological roles—pathological when chronically dysregulated in disease, yet physiologically beneficial when transiently elevated during exercise. PMID 37841263PMID 35113729
\nClinical Success: From Bench to Bedside
\nIL-6 pathway inhibition has achieved regulatory approval for multiple inflammatory conditions, establishing proof-of-concept that targeting exerkines can yield therapeutic benefit. PMID 32327746PMID 30995492 Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, has demonstrated clinical efficacy and gained approval for rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Castleman disease, and cytokine release syndrome. PMID 28778870PMID 35113729PMID 32327746 Siltuximab, an anti-IL-6 ligand antibody, is approved for Castleman disease and has shown promise in oncology applications. PMID 24076269PMID 25589616PMID 35969896
\nThese successes position IL-6 blockade as a validated therapeutic strategy, with emerging applications under investigation for neuromyelitis optica spectrum disorder, autoimmune encephalitis, COVID-19 pneumonia, and inflammatory bowel disease. PMID 37841263PMID 32327746PMID 37069261 Potential benefits in cardiometabolic diseases—including type 2 diabetes, chronic kidney disease, and cardiovascular disease—are being explored, though the benefit-risk profile in these settings requires further validation. PMID 35212585
\nMechanistic Basis and Therapeutic Refinement
\nThe therapeutic rationale centers on IL-6's role as a pleiotropic cytokine that, when chronically elevated, drives pathological inflammation through JAK/STAT pathway activation, acute-phase protein induction, and immune cell recruitment. PMID 35969896PMID 29725131 However, not all IL-6 signaling is pathological. IL-6 signals through two distinct pathways: classical signaling via membrane-bound IL-6 receptor (protective and homeostatic) and trans-signaling via soluble IL-6 receptor (predominantly pro-inflammatory). PMID 37069261PMID 29725131
\nThis mechanistic understanding has enabled next-generation therapeutic strategies that selectively block IL-6 trans-signaling while preserving beneficial classical signaling, potentially improving the therapeutic index by maintaining homeostatic functions. PMID 37069261 Such selectivity may address current limitations, including the observation that certain inflammatory diseases do not respond to pan-IL-6 blockade and that cancer trials have yielded disappointing results despite biological rationale, likely due to tumor cell plasticity and compensatory signaling. PMID 30995492PMID 25589616
\nResolving the Paradox: Context Determines Outcome
\nThe dual nature of IL-6—detrimental in chronic inflammatory disease yet beneficial during acute exercise—highlights a fundamental principle in exerkine biology: context, magnitude, and duration of signaling determine physiological outcome. PMID 35113729PMID 37841263 During exercise, transient IL-6 elevation from contracting skeletal muscle mediates beneficial metabolic adaptations including enhanced glucose uptake, lipid oxidation, and anti-inflammatory effects, without triggering the chronic inflammatory cascade observed in disease states. PMID 32327746
\nThis context-dependency suggests that therapeutic IL-6 inhibition for chronic inflammatory conditions does not negate the beneficial effects of exercise-induced IL-6, as the temporal dynamics, source tissue, and downstream signaling differ fundamentally between these scenarios. PMID 35113729PMID 32327746 Understanding this distinction is critical for therapeutic development and may inform strategies to selectively target pathological IL-6 signaling while preserving its physiological roles. PMID 29725131PMID 37069261
\nClinical perspective: IL-6 stands alone among exerkines as having achieved regulatory approval for therapeutic applications, validating the exerkine concept while simultaneously demonstrating the complexity of translating exercise biology into pharmacological intervention. PMID 28778870PMID 30995492
" }, "pmids": [ "12205025", "18923185", "21799452", "24076269", "24655147", "25589616", "28778870", "29725131", "30995492", "32327746", "32563931", "32864098", "33872590", "35113729", "35212585", "35969896", "37069261", "37841263" ] }, { "id": "igf-1", "shortName": "IGF-1", "fullName": "Insulin-like Growth Factor 1 (IGF-1)", "tier": 1, "sourceTissue": "Liver (hepatokine); local muscle", "moleculeType": "Peptide hormone", "keyPathway": "IGF1R; MAPK, PI3K", "domains": { "cv": null, "met": null, "neuro": null, "msk": "primary", "inflam": null, "onco": null }, "sections": { "definition": "Insulin-like growth factor 1 (IGF-1) is a peptide hormone primarily produced by the liver in response to growth hormone (GH) that mediates growth, cellular proliferation, differentiation, and survival throughout the body. PMID 33557137PMID 33962049 It also functions in an autocrine and paracrine manner when produced locally in various tissues. PMID 40442384PMID 23148873
", "biologicalFunction": "IGF-1 exerts its biological effects by binding to the type 1 IGF-1 receptor (IGF1R), a receptor tyrosine kinase that activates downstream signaling pathways, predominantly the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. PMID 40442384 These pathways regulate cellular anabolism, protein synthesis, and cell survival. PMID 8874492 In circulation, approximately 98% of IGF-1 is bound to IGF binding proteins (IGFBPs), which modulate its bioavailability and tissue access. PMID 33557137PMID 33962049 Beyond its well-established role in promoting postnatal growth—contributing to approximately 83% of postnatal growth when combined with GH's direct effects—IGF-1 influences glucose metabolism, has neuroprotective and cardioprotective properties, and plays roles in neurogenesis and synaptic plasticity. PMID 36848915PMID 40442384PMID 21042815
", "exerkineClassification": "IGF-1 is considered an exerkine, a molecule released in response to exercise that mediates beneficial adaptations to physical activity. PMID 20010132PMID 20010131 The evidence supporting this classification includes that local IGF-1 production is consistently upregulated with both acute and chronic exercise. PMID 20010131 IGF-1 appears to play a central role in exercise-induced cellular anabolism, muscle and bone remodeling, and body composition changes. PMID 20010132PMID 20010131 While circulating IGF-1 levels may decrease or remain unchanged with certain training regimens, local tissue production increases, suggesting that locally produced IGF-1 is particularly important for mediating exercise adaptations. PMID 20010131 The IGF-1 system has been described as \"an important and central hormonal axis that plays a significant role concerning cellular anabolism\" in the context of physical activity. PMID 20010132
", "therapeuticPotential": "Growth disorders represent the most established therapeutic application. IGF-1 (mecasermin) is FDA-approved for treating growth failure in pediatric patients with severe primary IGF-1 deficiency or growth hormone gene deletion who have developed neutralizing antibodies to growth hormone. (PMID: FDA Orange Book) Clinical studies demonstrate that recombinant human IGF-1 effectively promotes linear growth in children with growth hormone insensitivity syndrome (GHIS), including Laron syndrome, though it does not fully restore normal growth rates compared to growth hormone replacement in GH deficiency. PMID 15231299PMID 19198769PMID 36446332
\nMetabolic and insulin-resistant conditions show significant promise. IGF-1 improves glycemic control in both type 1 and type 2 diabetes mellitus by enhancing insulin sensitivity and reducing glucose levels. PMID 8116999PMID 15231299PMID 15860416 In patients with non-insulin-dependent diabetes, IGF-1 reduced fasting blood glucose by approximately 30% and serum insulin concentrations by more than 50%, while substantially decreasing triglyceride levels. PMID 22682639PMID 7821734 IGF-1 has also proven effective in severe insulin resistance syndromes. PMID 15231299PMID 22682639PMID 7821734
\nAnabolic and catabolic conditions represent another therapeutic avenue. IGF-1's protein-sparing and anabolic properties are being evaluated for osteoporosis, catabolic states (burns, post-operative recovery, AIDS muscle wasting), chronic inflammatory disorders (Crohn's disease, cystic fibrosis), and nutritional disorders. PMID 8116999PMID 19198769PMID 18031115
\nCentral nervous system disorders are emerging targets. IGF-1 stimulates neuronal survival and myelin synthesis, with preclinical and clinical studies showing potential efficacy in autism spectrum disorder, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord injury, and other neurodevelopmental conditions. PMID 19198769PMID 26780584
\nLiver cirrhosis and aging-related conditions have been identified as states of IGF-1 deficiency where replacement therapy may provide clinical benefit. PMID 23148873
\nThe most common adverse effects include hypoglycemia (controlled by administration with meals), lymphoid tissue hyperplasia, body fat accumulation, and facial coarsening. PMID 19198769 Long-term safety concerns include IGF-1's anti-apoptotic properties and potential cancer risk. PMID 19198769
" }, "pmids": [ "15231299", "15860416", "18031115", "19198769", "20010131", "20010132", "21042815", "22682639", "23148873", "26780584", "33557137", "33962049", "36446332", "36848915", "40442384", "7821734", "8116999", "8874492" ] }, { "id": "vegf", "shortName": "VEGF", "fullName": "Vascular Endothelial Growth Factor (VEGF)", "tier": 1, "sourceTissue": "Skeletal muscle (myokine)", "moleculeType": "Growth factor", "keyPathway": "VEGFR1/2; PI3K/Akt, MAPK", "domains": { "cv": null, "met": null, "neuro": null, "msk": null, "inflam": null, "onco": "primary" }, "sections": { "definition": "β-Hydroxybutyrate (BHB) is the predominant ketone body synthesized in the liver during periods of low glucose availability, serving both as an alternative energy substrate and as a signaling molecule with diverse biological functions. BHB is produced through ketogenesis, primarily in hepatic mitochondria, and becomes elevated during fasting, caloric restriction, ketogenic diets, and exercise. PMID 32525972PMID 40583323PMID 28826372PMID 41418322PMID 41109663
", "biologicalFunction": "Beyond its role as an energy source, BHB functions as a signaling metabolite that regulates gene expression, inflammation, and cellular stress responses through multiple mechanisms. BHB acts as an endogenous inhibitor of histone deacetylases (HDACs), thereby influencing chromatin structure and gene transcription. PMID 28826372PMID 24140022PMID 32525972 Additionally, BHB serves as a substrate for lysine β-hydroxybutyrylation (Kbhb), a post-translational modification that modulates chromatin accessibility, gene regulation, and cellular metabolism in both histone and non-histone proteins. PMID 41418322PMID 37575967 BHB also binds to the G-protein-coupled receptor GPR109A (also known as hydroxyl-carboxylic acid receptor), mediating anti-inflammatory and anti-lipolytic effects. PMID 32525972PMID 40305364
", "exerkineClassification": "BHB is considered an exerkine—a signaling molecule released in response to exercise that exerts systemic effects. Ketone bodies are oxidized as fuel during exercise, become markedly elevated during post-exercise recovery, and the capacity to utilize ketone bodies is enhanced in exercise-trained skeletal muscle. PMID 40157803PMID 27861911 Exercise increases BHB production, and this molecule can cross the blood-brain barrier to influence neuronal function, synaptic plasticity, and neuroprotection. PMID 40583323PMID 40157803 As an exerkine, BHB mediates beneficial effects of exercise on the brain through both direct (autonomous) effects after crossing the blood-brain barrier and indirect (non-autonomous) effects on peripheral tissues. PMID 40157803
\nBHB's therapeutic potential extends to cardiovascular function, where it dramatically increases myocardial blood flow and cardiac output, as well as to neuroprotection in conditions such as epilepsy and dementia. PMID 32525972PMID 40583323 Its ability to modulate autophagy, reduce oxidative stress, and regulate mitochondrial function positions BHB as a key metabolic mediator linking environmental factors like diet and exercise to cellular homeostasis. PMID 40583323PMID 40305364
", "therapeuticPotential": "Cardiovascular Applications: BHB demonstrates significant cardioprotective effects in heart failure. It serves as an efficient cardiac fuel that improves myocardial blood flow and cardiac output in both control subjects and heart failure patients. PMID 32525972 The therapeutic mechanisms include enhanced mitochondrial oxidative metabolism, reduced oxidative stress, and modulation of cardiac fuel utilization. PMID 36996176 BHB also promotes vasodilation, reduces inflammation and fibrosis, and supports angiogenesis. PMID 36996176
\nNeurological and Cognitive Benefits: BHB crosses the blood-brain barrier to provide neuroprotection through multiple mechanisms. It enhances cognitive processes including learning and memory by modulating synaptic plasticity and neurotransmitter levels. PMID 40583323 In adults with obesity, 14 days of BHB supplementation improved cerebral blood flow by 11-12% and enhanced cognitive performance on digit-symbol substitution testing. PMID 34605026 BHB shows promise for neurodegenerative diseases like Alzheimer's and Parkinson's by supporting proteostasis, stimulating autophagy, and reducing protein aggregation. PMID 37575967 Its use in epilepsy to reduce seizure frequency is well-established, with potential applications in other neurological conditions including dementia. PMID 32525972
\nMetabolic and Diabetes Treatment: BHB exhibits protective effects against type 2 diabetes mellitus by regulating glucose and lipid metabolism, preserving pancreatic β-cell integrity, and improving insulin resistance. PMID 41201041 It reduces oxidative stress, controls inflammatory responses and endoplasmic reticulum stress, while regulating mitochondrial biogenesis and autophagy. PMID 41201041 Clinical studies demonstrate that regulating BHB levels can influence body weight, fasting blood glucose, insulin resistance, and memory in diabetic patients. PMID 41201041
\nEpigenetic and Signaling Mechanisms: Beyond its role as an energy substrate, BHB functions as a signaling molecule with epigenetic regulatory capacity. It acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience. PMID 40583323PMID 37928021 BHB also mediates lysine β-hydroxybutyrylation (Kbhb), a post-translational modification that links ketone metabolism to gene regulation, chromatin accessibility, and cellular metabolism. PMID 41418322 These epigenetic effects are crucial in diabetes, cancer, and cardiovascular disease contexts. PMID 37928021
\nAnti-inflammatory and Antioxidant Properties: BHB inhibits the NLRP3 inflammasome in immune cells, reducing inflammatory cytokine production. PMID 32525972PMID 27826689 It reduces oxidative stress by altering mitochondrial NAD/NADH ratios and decreasing reactive oxygen species production. PMID 27826689 These properties contribute to its therapeutic effects across multiple organ systems including neurons, muscle, liver, and cardiovascular tissues. PMID 38193855
\nClinical Translation: Multiple approaches exist to elevate circulating BHB therapeutically, including ketogenic diets, exogenous ketone salts and esters, and biologically synthesized D-3HB. PMID 34415393 Recent development of ketone monoester supplements shows particular promise, allowing elevation of plasma BHB without strict dietary restriction. PMID 34605026 The molecule is generally well-tolerated and appears safe for therapeutic use. PMID 34605026
" }, "pmids": [ "24140022", "27826689", "27861911", "28826372", "32525972", "34415393", "34605026", "36996176", "37575967", "37928021", "38193855", "40157803", "40305364", "40583323", "41109663", "41201041", "41418322" ] }, { "id": "nrg", "shortName": "NRG1", "fullName": "Neuregulin 1 (NRG1)", "tier": 2, "sourceTissue": "Heart; skeletal muscle", "moleculeType": "Growth factor", "keyPathway": "ErbB2/4; PI3K/Akt, MAPK/ERK, mTOR", "domains": { "cv": "primary", "met": null, "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Neuregulins (Nrgs) are a family of multifunctional polypeptide growth factors that primarily act by activating tyrosine kinase receptors, specifically the ErbB receptor family PMID 41213606.
", "biologicalFunction": "Cardiovascular Disease
\nRecombinant NRG-1 has demonstrated beneficial effects in heart failure in both animal models and human clinical trials (1-5, PMID 33063822PMID 36120374PMID 23104879PMID 21631420PMID 23384772. Two distinct forms of recombinant NRG-1 improve cardiac function in patients with systolic heart failure (1, PMID 33063822. Phase I and II clinical trials have shown that NRG-1 is safe and improves cardiac function in chronic heart failure patients (4-5, PMID 21631420PMID 23384772. The therapeutic mechanisms include promoting cardiomyocyte survival and proliferation, maintaining myofibril structure, counterbalancing excessive β-adrenergic signaling, and promoting angiogenesis (4, 6, PMID 21631420PMID 22427524.
\nBeyond heart failure, NRG-1 shows promise in multiple cardiovascular conditions including diastolic heart failure, atherosclerosis prevention, diabetic cardiovascular complications, and sepsis-associated cardiac dysfunction (1, PMID 33063822. NRG-1 can repair the heart in atherosclerosis, myocardial infarction, ischemia-reperfusion injury, and cardiomyopathy by regulating cardiac inflammation, oxidative stress, and necrotic apoptosis (2, PMID 36120374.
\nNeurological and Neurodegenerative Diseases
\nNRG-1 represents a potential neuroprotective treatment for ischemic stroke, with a therapeutic window exceeding 13 hours in preclinical studies (7, PMID 38638304. It significantly reduces ischemia-induced neuronal death, neuroinflammation, and oxidative stress in rodent stroke models (7, PMID 38638304. NRG-1 has been shown to be safe in human patients in cardiac trials, supporting its potential translation to stroke treatment (7, PMID 38638304.
\nNRG/ErbB signaling shows therapeutic potential in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) (8-9, PMID 33897409PMID 40254133. The pathway regulates differentiation, migration, and myelination, and plays roles in neuroprotection and remyelination following CNS injury (10, PMID 31229498. Recent discoveries include human pedigrees where autosomal dominant frontotemporal lobar degeneration/ALS potentially results from ERBB4 mutations (9, PMID 40254133.
\nNervous System Injury and Repair
\nNRG-1/ErbB signaling is critical for both peripheral and central nervous system repair (10, PMID 31229498. It modulates glial and immune responses while fostering neuroprotection and remyelination in CNS injury (10, PMID 31229498. The pathway also regulates synaptic plasticity at glutamatergic, GABAergic, and dopaminergic synapses, which is essential for learning, memory, and complex behaviors (11-12, PMID 31906113PMID 39923224.
" }, "pmids": [ "21631420", "22427524", "23104879", "23384772", "31229498", "31906113", "33063822", "33897409", "36120374", "38107476", "38638304", "38786764", "39522716", "39923224", "40254133", "40818821", "41213606" ] }, { "id": "gdnf", "shortName": "GDNF", "fullName": "Glial Cell Line-Derived Neurotrophic Factor (GDNF)", "tier": 2, "sourceTissue": "Skeletal muscle; spinal cord", "moleculeType": "Neurotrophic factor", "keyPathway": "RET/GFRα1", "domains": { "cv": null, "met": null, "neuro": "primary", "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Glial Cell Line-Derived Neurotrophic Factor (GDNF) is a potent neurotrophic factor that supports the maintenance and survival of mid-brain dopaminergic and spinal motor neurons through specific signaling pathways involving the Ret proto-oncogene and GFRα1 PMID 39456173. Recognized as an exerkine due to its intensity-dependent upregulation in skeletal muscle and the spinal cord following physical activity, GDNF offers significant therapeutic potential for neuroprotection and neurorestoration in Parkinson's and Alzheimer's diseases PMID 39456173PMID 38393277PMID 34782555.
", "biologicalFunction": "GDNF is classified as an exerkine because its expression in skeletal muscle and the spinal cord is modulated by physical activity, following a dose-response pattern based on exercise intensity.
\n1. Parkinson’s Disease (PD)
\n2. Other Neurodegenerative Conditions
\n3. Psychiatric Disorders and Addiction
\n4. Regenerative Medicine and Peripheral Repair
\n5. Oncology: A Double-Edged Sword
\n6. Emerging Isoforms
\nFollistatin is a secreted, single-chain glycosylated protein that functions as a high-affinity binding protein for members of the transforming growth factor-β (TGF-β) superfamily. PMID 29020616PMID 9799587 The molecule consists of a 63-residue N-terminal domain followed by three repeating follistatin domains (FSD1, FSD2, and FSD3), each containing 10 cysteine residues. PMID 11279126 Three major isoforms exist (FST288, FST303, and FST315) that differ in their tissue distribution and cell-surface binding properties, with FST288 showing the strongest heparin-binding affinity. PMID 16627583
\nFollistatin is expressed in various tissues throughout the body, including the liver, ovaries, pituitary gland, skeletal muscle, and reproductive tissues. PMID 29020616PMID 9799587 The protein was first identified in 1987 as a follicle-stimulating hormone (FSH) inhibiting substance in ovarian follicular fluid, though subsequent research has revealed much broader biological roles. PMID 9799587
", "biologicalFunction": "Follistatin's primary biological function is binding and neutralizing members of the TGF-β superfamily, particularly activin, myostatin, and bone morphogenetic proteins (BMPs). PMID 29020616PMID 30874767 The protein binds these ligands with high affinity, blocking their interaction with cell-surface receptors and thereby preventing downstream signaling. PMID 16482217
\nThe mechanism of action involves follistatin wrapping around the target ligand and physically blocking the type II receptor-binding site. PMID 16482217 For activin specifically, the second follistatin domain (FSD2) mediates the high-affinity interaction, with arginine 192 serving as a key residue that inserts between activin's \"fingers\". PMID 16482217 Interestingly, myostatin binding depends more heavily on FSD1, demonstrating differential ligand specificity among the follistatin domains. PMID 18535106
\nBeyond its extracellular antagonism activity, follistatin can also translocate into the nucleus under certain stress conditions to maintain cellular homeostasis through mechanisms independent of its ligand-binding function. PMID 29020616
\nThe biological consequences of follistatin's neutralizing activity include:
\nCell-surface binding via heparin sulfate proteoglycans is critical for follistatin's biological activity, as it concentrates the protein locally and facilitates irreversible ligand neutralization and lysosomal degradation. PMID 16627583PMID 21353885
", "exerkineClassification": "Follistatin is considered an exerkine, specifically a contraction-induced hepatokine based on evidence that it is secreted from the liver in response to exercise. PMID 21068158
\nThe key evidence supporting follistatin as an exerkine includes:
\nMuscle Disorders and Regeneration: Follistatin shows promise for treating Duchenne muscular dystrophy (DMD) through its ability to antagonize myostatin and activin, negative regulators of muscle growth PMID 35850122. An AAV1-mediated intramuscular gene therapy (rAAV1.CMV.huFollistatin344) is being evaluated in phase 1/2 trials for DMD, with results awaited PMID 35850122. Additionally, engineered follistatin variants demonstrate robust muscle regeneration and improved muscle function in preclinical models of muscle injury and atrophy PMID 21689628PMID 24627466.
\nFollistatin improves skeletal muscle healing by enhancing muscle regeneration, promoting angiogenesis, and reducing fibrosis PMID 21689628. In transgenic mice overexpressing follistatin, significantly greater myofiber regeneration and less fibrosis formation occurred after skeletal muscle injury compared to wild-type mice PMID 21689628. Systemic administration of engineered follistatin variants increases lean muscle mass and accelerates restoration of myofibers and muscle function after injury PMID 24627466.
\nInflammatory and Fibrotic Diseases: Follistatin has anti-inflammatory and antifibrotic properties that make it a therapeutic target for conditions including sepsis, liver fibrosis, acute lung injury, asthma, and ischemia-reperfusion injury PMID 23541927. Activin levels increase in both acute and chronic inflammation, and inhibition of activin action through follistatin can reduce inflammation, damage, fibrosis, and morbidity/mortality in various disease models PMID 23541927PMID 21353885.
\nMetabolic Disorders: Intravascular follistatin gene delivery improves glycemic control in mouse models of type 2 diabetes by reducing serum activin B concentrations, promoting insulinemia, and maintaining functional pancreatic β-cells PMID 32141144. Follistatin overexpression markedly increases insulin-stimulated glucose uptake and completely normalizes muscle glucose uptake in insulin-resistant diet-induced obese mice PMID 31402604.
\nPharmacokinetic Optimization: Native follistatin has rapid heparin-mediated hepatic clearance that limits its therapeutic potential PMID 29752426. Engineered variants with reduced heparin-binding affinity or Fc fusion proteins demonstrate 20- to 100-fold improvements in exposure and antibody-like pharmacokinetic profiles, making them more suitable for therapeutic development PMID 29752426PMID 23249626.
" }, "pmids": [ "11279126", "16482217", "16627583", "18535106", "21068158", "21353885", "21689628", "23249626", "23541927", "24627466", "26652766", "29020616", "29752426", "30563942", "30694975", "30874767", "31402604", "32141144", "35850122", "9799587" ] }, { "id": "lac-phe", "shortName": "Lac-Phe", "fullName": "N-lactoyl-phenylalanine (Lac-Phe)", "tier": 2, "sourceTissue": "Immune/epithelial cells (CNDP2 enzyme)", "moleculeType": "Metabolite", "keyPathway": "Central appetite centers (hypothalamus)", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "N-lactoyl-phenylalanine (Lac-Phe) is a novel, exercise-inducible metabolite and signaling moiety, discovered through untargeted metabolomics, that is synthesized from the condensation of lactate and phenylalanine PMID 39136551PMID 39456173PMID 36633863.
", "biologicalFunction": "Lac-Phe is classified as an exerkine based on multi-tissue metabolomic mapping that shows it is a highly dynamic molecular transducer of physical activity:
\nFrom PMID 39456173: Li et al. [235] began their search for exerkines by performing an exercise-induced metabolomics assessment of blood plasma in mice. One of the most significantly induced non-targeted metabolites was shown to be N-lactoyl-phenylalanine (Lac-Phe) [235]. They then reported that the enzyme responsible for the synthesis of Lac-Phe, CNDP2 (cytosolic non-specific dipeptidase, also known as carnosine dipeptidase 2), was found predominantly in epithelial cells and macrophages [235]. CNDP2 is found in the gut and kidney [236]. Although the mechanism is still being determined, Lac-Phe suppresses appetite and food intake [235,236]. Ultimately, the result of exercise generates Lac-Phe, which leads to a reduction in body weight. Interestingly, metformin (a drug widely used in diabetes and off-label in PD) mediates weight loss through Lac-Phe [237].
\nThe most extensively studied therapeutic application is in obesity and metabolic disease. The most extensively studied therapeutic application is in obesity and metabolic disease. Lac-Phe suppresses appetite and reduces body weight in diet-induced obese mice, with chronic administration improving glucose homeostasis and decreasing adiposity. PMID 35705806 These effects appear mediated through central mechanisms, including inhibition of orexigenic agouti-related peptide neurons. PMID 41547294 The first human clinical trial in individuals with obesity began dosing in 2025, evaluating appetite suppression and glucose-lowering effects. PMID 41547294
\nAnti-inflammatory and neuroprotective effects represent another therapeutic avenue. Lac-Phe promotes anti-inflammatory macrophage polarization, conferring protection in murine models of colitis and spinal cord injury. PMID 41547294 In spinal cord injury specifically, Lac-Phe modulates lipid metabolism in microglia/macrophages via the AMPK-PGC1α-PPARγ pathway, shifts polarization toward the anti-inflammatory M2 phenotype, and significantly improves motor function recovery. PMID 40579710
\nCardiovascular applications are emerging, with Lac-Phe demonstrating blood pressure-lowering effects in angiotensin II-induced hypertensive mice, alleviating increases in both systolic and diastolic blood pressure. PMID 41478213
\nHowever, important caveats exist. High-concentration Lac-Phe exposure in cell models impairs insulin signaling, increases pro-inflammatory cytokine secretion, and disrupts mitochondrial respiration. PMID 40862774 These findings underscore the necessity of comprehensive risk assessment and dose optimization before clinical translation. PMID 40862774 The therapeutic window and optimal dosing strategies remain to be fully defined as this field advances from preclinical models to human trials. PMID 41547294
" }, "pmids": [ "35304603", "35705806", "36633863", "37247469", "38917635", "39136551", "39456173", "40579710", "40862774", "41478213", "41547294" ] }, { "id": "gdf15", "shortName": "GDF15", "fullName": "Growth Differentiation Factor 15 (GDF15)", "tier": 2, "sourceTissue": "Multi-tissue (stress-induced)", "moleculeType": "Cytokine (TGF-β superfamily)", "keyPathway": "GFRAL/RET (hindbrain)", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "GDF15 is a stress-induced cytokine and divergent member of the transforming growth factor-β (TGF-β) superfamily that functions as a multifunctional signaling molecule. PMID 33172749PMID 34836750 It is also known by alternative names including macrophage inhibitory cytokine-1 (MIC-1) and non-steroidal anti-inflammatory drug-activated gene (NAG-1). PMID 34836750PMID 31663791
\nGDF15 is normally expressed at low levels in most tissues under physiological conditions, with the notable exception of the placenta where it is abundant. PMID 32508832 However, it is prominently induced in response to cellular stress, tissue injury, inflammation, mitochondrial dysfunction, oxidative stress, hypoxia, and telomere erosion. PMID 33172749PMID 40825163PMID 28062617 The GDF15 gene promoter contains two binding sites for the p53 transcription factor, which mediates its upregulation in response to various cellular stressors. PMID 32466889
", "biologicalFunction": "GDF15 signals through the GFRAL (glial-derived neurotrophic factor family receptor α-like) receptor, which is selectively expressed in hindbrain neurons, particularly in the area postrema and nucleus tractus solitarius. PMID 33172749PMID 34849709 This receptor signals through the coreceptor RET to mediate GDF15's effects. PMID 33172749
\nThe primary established physiological functions of GDF15 include:
\nThe effects of GDF15 can be beneficial or detrimental depending on timing, magnitude, and duration of signaling. PMID 40825163 While it appears protective in acute stress and tissue injury, chronically elevated levels are associated with poor outcomes in cancer, cardiovascular disease, and metabolic disorders. PMID 40825163PMID 28062617
", "exerkineClassification": "The classification of GDF15 as a functional exerkine remains controversial, with current evidence suggesting it may be a \"coincidental bystander\" rather than an essential mediator of exercise benefits. PMID 34849709
\nEvidence against functional exerkine role:
\nLack of causal relationship: Studies using GDF15-deficient mice demonstrate that while GDF15 is associated with exercise-induced increases in corticosterone and indices of lipid utilization (NEFA, beta-hydroxybutyrate), these metabolic changes occur normally in GDF15-/- mice, indicating the associations are not causal. PMID 39480267
\nUncertain physiological significance: The jury remains out on whether exercise-induced GDF15 has functional implications for appetite and metabolism or whether it simply reflects cellular stress without mediating beneficial adaptations. PMID 34849709
\nContext-dependent effects: GDF15 production in muscle can be induced both by beneficial exercise and by pathological states such as sarcopenia and mitochondrial myopathy, suggesting it may be a general stress marker rather than a specific exercise mediator. PMID 34831213
\nCurrent consensus suggests that while GDF15 increases with exercise and associates with metabolic changes, definitive evidence for its role as a functional exerkine mediating exercise benefits is lacking. PMID 34849709PMID 39480267PMID 39472228
", "therapeuticPotential": ", GDF-15 shows promise as a therapeutic target due to its ability to suppress appetite and reduce body weight through binding to GFRAL (glial cell-derived neurotrophic factor family receptor $alpha$-like) in the hindbrain. PMID 34381196 This mechanism is largely independent of other appetite-regulating hormones like leptin or GLP-1, making it an appealing candidate for treating obesity, type 2 diabetes, and non-alcoholic fatty liver disease. PMID 34381196 Several GDF-15 analogs/mimetics are currently under development. PMID 39000420
\nIn cardiovascular disease, GDF-15 demonstrates cardioprotective properties through its autocrine/paracrine effects, which are antioxidative, anti-inflammatory, and antiapoptotic. PMID 34445593 GDF-15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and myocardial infarction, suggesting a protective role in cardiac injury. PMID 34445593PMID 33317942 Studies support its potential use by modulating metabolic activity and promoting adaptive angiogenesis and cardiac regenerative processes. PMID 34445593
\nIn cancer, the therapeutic potential is more complex and context-dependent. While GDF-15 may have protective effects in early disease stages, it appears to promote tumor growth in later stages of malignant cancer. PMID 32936319PMID 34836750 This has led to development of GDF-15-targeting monoclonal antibodies as potential cancer therapeutics. PMID 39000420
\nIn neurologic disease, emerging evidence suggests GDF-15 may have neuroprotective roles against neurodegeneration, though its role as a therapeutic target in neurologic disorders is yet to be established. PMID 40825163
\nThe anti-inflammatory and immunomodulatory properties of GDF-15 have also positioned it as a potential immune checkpoint target for cancer immunotherapy. PMID 32508832
" }, "pmids": [ "28062617", "31663791", "32466889", "32508832", "32936319", "33172749", "33317942", "34381196", "34445593", "34831213", "34836750", "34849709", "36542831", "39000420", "39472228", "39480267", "40825163" ] }, { "id": "bdnf", "shortName": "BDNF", "fullName": "Brain-Derived Neurotrophic Factor (BDNF)", "tier": 2, "sourceTissue": "Brain; skeletal muscle", "moleculeType": "Neurotrophin", "keyPathway": "TrkB; PI3K/Akt, MAPK/ERK, PLCγ", "domains": { "cv": null, "met": null, "neuro": "primary", "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Brain-Derived Neurotrophic Factor (BDNF) is a pleiotropic neurotrophin and myokine upregulated by physical exercise that activates TrkB receptor signaling to promote cell survival, synaptic plasticity, and mitochondrial bioenergetics PMID 40869331, 2025; PMID 39456173PMID 36417200. It serves as a vital therapeutic target for neurodegenerative and metabolic conditions due to its ability to potentially facilitate neurogenesis, reduce neuroinflammation, and enhance lipid oxidation through the AMPK-PGC-1α and NF-κB pathways PMID 40869331PMID 40210118PMID 38699186PMID 34782555.
", "biologicalFunction": "BDNF is classified as an exerkine (specifically a neurokine and myokine) because its expression and secretion are significantly upregulated in response to physical activity, facilitating crosstalk between organs.
\n1. Neuropsychiatric Disorders: Depression and Anxiety
\n2. Neurodegenerative Diseases
\n3. Traumatic Brain Injury (TBI) and Stroke
\n4. Novel Delivery Systems
\n5. Lifestyle and Non-Pharmacological Interventions
\nIC7Fc represents a novel paradigm in exerkine-based therapeutics: a genetically engineered designer cytokine that combines structural and functional elements of IL-6 (discussed above) with ciliary neurotrophic factor (CNTF) to harness metabolic benefits while circumventing inflammatory complications. PMID 41134879PMID 32563931 CNTF is a 22-kDa neurotrophic cytokine that promotes neuronal survival and regulates energy metabolism through binding to a tripartite receptor complex (CNTFRα/LIFRβ/gp130), activating JAK/STAT, MAPK, and PI3K/AKT signaling pathways. PMID 36065930PMID 7809179 While CNTF demonstrates potent metabolic effects including body weight reduction and improved glucose homeostasis, its clinical development has been limited by side effects and the fact that it is not secreted by muscle in response to exercise. PMID 36065930PMID 15542451
", "biologicalFunction": "Content pending.
", "exerkineClassification": "The creation of IC7Fc exploits the shared signaling biology of IL-6 and CNTF, both of which signal through the common receptor component gp130 despite using different receptor complexes. PMID 28620096PMID 1617725 The engineering strategy leverages the modular organization of cytokine receptor recognition sites, which permits transfer of binding domains between IL-6 and CNTF despite limited sequence homology. PMID 10207005 By fusing an IL-6/CNTF chimeric cytokine to an Fc domain, IC7Fc achieves extended half-life and improved pharmacokinetics while maintaining metabolic activity. PMID 41134879
\nCritically, IC7Fc signals exclusively through membrane-bound receptors (classical signaling), bypassing the IL-6 trans-signaling pathway that mediates pro-inflammatory effects in chronic disease. PMID 41134879PMID 32563931 This selective signaling mechanism allows IC7Fc to deliver the beneficial metabolic effects observed with exercise-induced IL-6 elevation—including enhanced energy expenditure, improved glucose homeostasis, and favorable lipid metabolism—without triggering the inflammatory cascades associated with pathological IL-6 elevation. PMID 41134879
", "therapeuticPotential": "In preclinical studies, IC7Fc demonstrated marked reductions in plasma triglycerides and total cholesterol through inhibition of hepatic de novo lipogenesis, increased bile acid synthesis, and decreased apolipoprotein B production, resulting in substantially reduced atherosclerotic lesion formation. PMID 41134879 Additionally, IC7Fc showed beneficial effects on type 2 diabetes progression and other metabolic parameters. PMID 41134879PMID 32563931 These findings establish IC7Fc as proof-of-concept that rational engineering of exerkine biology can yield selective therapeutic agents that recapitulate the beneficial effects of exercise-induced signaling while minimizing risks associated with chronic cytokine administration.
" }, "pmids": [ "10207005", "15542451", "1617725", "28620096", "32563931", "36065930", "41134879", "7809179" ] }, { "id": "lactate", "shortName": "Lactate", "fullName": "Lactate", "tier": 2, "sourceTissue": "Skeletal muscle (metabolite)", "moleculeType": "Metabolite", "keyPathway": "HCAR1 (GPR81); histone lactylation", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": "established" }, "sections": { "definition": "Lactate is a three-carbon carboxylic acid (the anionic form of lactic acid) that serves as a central metabolite in cellular energy metabolism and a signaling molecule with diverse physiological functions. PMID 36633863PMID 29617642PMID 33566386
", "biologicalFunction": "Lactate is continuously produced under fully aerobic conditions through glycolysis, not merely as a byproduct of anaerobic metabolism as historically believed. PMID 29617642PMID 33566386PMID 32113910 Its biological roles include:
\nEnergy metabolism: Lactate functions as a major oxidative fuel through the \"lactate shuttle\" mechanism, where it is transported between producer (driver) and consumer (recipient) cells to fuel mitochondrial respiration. PMID 36633863PMID 29617642PMID 33566386 It also serves as the primary gluconeogenic precursor in the liver. PMID 29617642PMID 32113910
\nCellular signaling: Lactate acts as a signaling molecule through multiple mechanisms, including binding to the G-protein coupled receptor HCAR1 (GPR81), modulating cellular redox state via the lactate/pyruvate ratio, and serving as a substrate for lactylation—a post-translational modification of histone and non-histone proteins that regulates gene expression. PMID 36633863PMID 37566665PMID 40073846PMID 41491598
\nMetabolic regulation: Lactate influences substrate partitioning by inhibiting lipolysis in adipose tissue and regulating mitochondrial fatty acid uptake, thereby controlling the balance between carbohydrate and fat oxidation. PMID 32113910
", "exerkineClassification": "Lactate is considered both a myokine and an exerkine—molecules secreted by skeletal muscle during contraction that exert autocrine, paracrine, and endocrine effects. PMID 36633863PMID 37842902 The evidence supporting this classification includes:
\nLactate concentrations increase substantially during exercise (rising more than 10-fold from resting levels) and mediate exercise-induced adaptations including mitochondrial biogenesis, angiogenesis, improved metabolic flexibility, and enhanced cognitive function. PMID 36633863PMID 33566386 As an exerkine, lactate facilitates communication between skeletal muscle and other organs, particularly the brain, where it may induce BDNF expression through SIRT1/2 and PGC-1α pathways. PMID 37842902 The intensity-dependent production of lactate during exercise, particularly from type IIb fast-twitch muscle fibers, supports its role as an exercise-derived signaling molecule. PMID 37842902
", "therapeuticPotential": "Hypertonic sodium lactate infusions have demonstrated promising therapeutic effects in several clinical settings. In traumatic brain injury, lactate treatment increases cerebral glucose availability, reduces intracranial pressure, and enhances cognitive recovery, while supporting up to 20% of cerebral energy metabolism. PMID 40440417 In cardiac applications, lactate infusion increases cardiac output, stroke volume, and ejection fraction, potentially benefiting heart failure patients. PMID 40440417
\nIn critical care, exogenous lactate—particularly hypertonic sodium lactate (HSL)—improves hemodynamics, reduces inflammation, and enhances organ function in sepsis, acute heart failure, and brain injury. PMID 41137071 The therapeutic mechanisms extend beyond simple energy provision to include anti-inflammatory effects, improved microcirculation, and metabolic homeostasis restoration. PMID 41137071
\nLactate functions as both an energy substrate and signaling molecule. It serves as a major energy source for mitochondrial respiration, the major gluconeogenic precursor, and influences gene expression through lactylation of histone proteins. PMID 29617642PMID 41491598 These dual metabolic and signaling roles underpin its therapeutic potential.
\nSafety data indicate that hypertonic lactate infusions are generally well tolerated, with minor electrolyte changes as the most common side effect. PMID 40440417PMID 35304646 However, large-scale randomized controlled trials are needed to establish optimal dosing, efficacy, and long-term safety profiles before widespread clinical adoption. PMID 41137071PMID 40440417
\nThe therapeutic applications span neonatal hypoxic-ischemic encephalopathy, cerebral ischemia, inflammatory conditions, and metabolic disorders, representing a paradigm shift from viewing lactate solely as a biomarker of poor prognosis to recognizing it as a potential therapeutic agent. PMID 37268250PMID 26036941PMID 36633863PMID 40821941PMID 40075490PMID 41137071
" }, "pmids": [ "26036941", "29617642", "32113910", "33566386", "35304646", "36633863", "37268250", "37566665", "37842902", "40073846", "40075490", "40440417", "40821941", "41137071", "41491598" ] }, { "id": "klotho", "shortName": "Klotho", "fullName": "Klotho", "tier": 2, "sourceTissue": "Kidney; brain choroid plexus", "moleculeType": "Glycoprotein", "keyPathway": "FGF23 coreceptor; Nrf2, FoxO", "domains": { "cv": null, "met": null, "neuro": null, "msk": null, "inflam": null, "onco": "primary" }, "sections": { "definition": "Klotho is an anti-aging transmembrane glycoprotein predominantly expressed in the kidneys, brain choroid plexus, and parathyroid glands. PMID 35903083PMID 30455427 The protein exists in multiple forms: full-length membrane-bound Klotho (mKl), which functions as an obligate coreceptor for fibroblast growth factor 23 (FGF23), and soluble Klotho (sKl), which circulates in blood, urine, and cerebrospinal fluid as a pleiotropic endocrine factor. PMID 29250031PMID 20375979
", "biologicalFunction": "Membrane-bound Klotho complexes with FGF receptors to enable FGF23 signaling, thereby regulating phosphate excretion, calcium homeostasis, and vitamin D metabolism in the kidneys. PMID 30455427PMID 21496980 Soluble Klotho functions independently of FGF23 by binding to ganglioside-enriched lipid rafts in cell membranes, where it modulates growth factor signaling pathways (particularly insulin/IGF-1 and PI3K/Akt), regulates ion channels and transporters, and suppresses oxidative stress through Nrf2 and FoxO pathways. PMID 35903083PMID 28069944 Klotho also inhibits pro-aging pathways including TGF-β, Wnt, and NF-κB signaling. PMID 35903083
", "exerkineClassification": "Klotho is considered an emerging exerkine, supported by systematic review and meta-analysis evidence. Chronic exercise training (minimum 12 weeks) significantly increases circulating soluble Klotho levels (Hedge's g 1.3, 95% CI 0.69-1.90, P \\< 0.0001), with this effect observed regardless of health condition or most exercise modalities, though protocol duration, volume, and intensity influence the magnitude of response. PMID 36266389 Both acute high-intensity aerobic exercise and chronic training protocols elevate Klotho concentrations in young and middle-aged adults. PMID 40157803 This exercise-induced increase in Klotho, combined with its systemic anti-aging and metabolic effects, establishes its classification as an exerkine—a factor released in response to physical activity that mediates beneficial health effects. PMID 36266389
", "therapeuticPotential": "Klotho has shown therapeutic promise in several disease categories. Preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. PMID 35903083 Specifically, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease, and has been shown to inhibit tumor growth in various animal models. PMID 28709936 In kidney disease, prevention of Klotho decline or supplementation of exogenous Klotho is associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification. PMID 28115282
\nMultiple therapeutic strategies to enhance Klotho levels have been identified. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), statins (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D, and pentoxifylline. PMID 35903083 Preclinical work demonstrated that antidiabetic drugs (metformin, GLP-1-based agents, GABA, PPAR-γ agonists) also enhanced Klotho. PMID 35903083 Additionally, s-Klotho protein injection was effective in preclinical studies, though it requires further investigation. PMID 35903083
\nKlotho's therapeutic mechanisms involve inhibition of four pathways linked to aging: transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt, and NF-κB, which can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. PMID 35903083 Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. PMID 35903083 The protein also serves as a potential autophagy regulator, playing a dual role in restoring autophagy to beneficial levels in various diseases. PMID 34737707
\nKlotho has potential clinical applications in diagnosis, prognosis, and replacement therapy for systemic Klotho deficiency, particularly in AKI and CKD. PMID 32699047 Soluble Klotho could serve as an early and sensitive marker of kidney function decline, as it starts to decline early in CKD stage 2. PMID 28115282
" }, "pmids": [ "20375979", "21496980", "28069944", "28115282", "28709936", "29250031", "30455427", "32699047", "34737707", "35903083", "36266389", "40157803" ] }, { "id": "irisin", "shortName": "Irisin", "fullName": "Irisin (FNDC5 cleavage product)", "tier": 3, "sourceTissue": "Skeletal muscle (myokine)", "moleculeType": "Peptide", "keyPathway": "Integrin αV/β5", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Irisin is a peptide hormone derived from proteolytic cleavage of the transmembrane protein fibronectin type III domain-containing protein 5 (FNDC5), primarily produced by skeletal muscle in response to exercise. PMID 33493316PMID 35872067PMID 41518679 It is considered an exerkine (specifically a myokine), as it is secreted during muscle contraction and mediates systemic effects of physical activity. PMID 40157803PMID 36843614
", "biologicalFunction": "Irisin's primary mechanism involves binding to the αV/β5 integrin receptor complex, activating signaling pathways that promote mitochondrial biogenesis, autophagy, and oxidative stress resistance. PMID 41518679 Its best-characterized function is inducing browning of white adipose tissue by increasing expression of uncoupling protein 1 (UCP1), thereby enhancing thermogenesis and energy expenditure. PMID 33493316PMID 35872067PMID 29608940 Beyond metabolic effects, irisin crosses the blood-brain barrier to induce brain-derived neurotrophic factor (BDNF) expression, supporting synaptic plasticity, neurogenesis, and cognitive function. PMID 40157803PMID 41518679PMID 36843614
\nAdditional biological roles include maintaining glucose homeostasis, promoting bone remodeling through enhanced osteoblast differentiation, stimulating myogenesis in skeletal muscle, and exerting cardioprotective effects via SIRT1/PGC-1α upregulation. PMID 41518679PMID 36225200PMID 40886173
", "exerkineClassification": "Irisin is classified as an exerkine because exercise activates PGC-1α in skeletal muscle, which stimulates FNDC5 production and subsequent irisin secretion. PMID 40157803PMID 36225200 Plasma irisin concentrations increase with acute exercise in an intensity-dependent manner, with levels remaining elevated for hours after prolonged intense exercise. PMID 40157803 This exercise-induced release and its role in mediating beneficial systemic effects of physical activity—including metabolic improvements, anti-inflammatory actions, and neuroprotection—firmly establish irisin as an exerkine. PMID 36843614PMID 35793739 While initially described as a myokine, irisin is also expressed in adipose and neural tissues, functioning through autocrine, paracrine, and endocrine mechanisms. PMID 41518679PMID 40886173
", "therapeuticPotential": "Irisin is an exercise-induced myokine that exerts therapeutic effects through multiple mechanisms, including anti-inflammatory, anti-apoptotic, and anti-oxidative properties. PMID 29414191 It promotes browning of white adipose tissue, regulates glucose and lipid homeostasis, and activates signaling pathways that enhance mitochondrial biogenesis, autophagy, and oxidative stress resistance. PMID 29414191PMID 41518679
\nMetabolic diseases represent a major therapeutic target. Irisin improves β-cell function and insulin secretion in diabetes, alleviates obesity through thermogenesis and energy expenditure, and shows promise for treating nonalcoholic fatty liver disease and polycystic ovary syndrome. PMID 39532260PMID 28394923PMID 35793739PMID 29170905 In type 2 diabetes models, irisin significantly reduced body weight and blood glucose while improving glucose tolerance. PMID 28394923
\nCardiovascular applications include ameliorating maladaptive cardiac hypertrophy and fibrosis, causing systemic vasodilation, and mitigating experimental heart failure through SIRT1/PGC-1α upregulation. PMID 40886173 Irisin reduces myocardial injury and protects against ischemia/reperfusion damage. PMID 39532260PMID 41452463
\nNeurodegenerative diseases benefit from irisin's ability to increase brain-derived neurotrophic factor in the hippocampus, reduce amyloid burden, limit α-synuclein pathology, and stabilize blood-brain barrier integrity. PMID 35872251PMID 41518679 Studies suggest protective effects in Alzheimer's disease, Parkinson's disease, and stroke. PMID 35793739PMID 35872251
\nAdditional therapeutic targets include bone metabolism (positive association with bone mineral density and inverse association with osteoporotic fractures), cancer, sarcopenia, and various inflammatory conditions. PMID 29170905PMID 35793739PMID 36225200PMID 41518679PMID 29414191PMID 39532260 Irisin also demonstrates anxiolytic and antidepressant effects. PMID 35872251
\nThe therapeutic mechanisms involve binding to integrin αV/β5 receptors and modulating programmed cell death pathways including apoptosis, ferroptosis, pyroptosis, and autophagy. PMID 41518679PMID 41452463
" }, "pmids": [ "28394923", "29170905", "29414191", "29608940", "33493316", "35793739", "35872067", "35872251", "36225200", "36843614", "39532260", "40157803", "40886173", "41452463", "41518679" ] }, { "id": "fstl1", "shortName": "FSTL1", "fullName": "Follistatin-like 1 (FSTL1)", "tier": 3, "sourceTissue": "Skeletal muscle; heart", "moleculeType": "Glycoprotein (SPARC family)", "keyPathway": "DIP2A; Smad2/3, PI3K/AKT, MAPK", "domains": { "cv": "primary", "met": null, "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "is a secreted glycoprotein belonging to the family of secreted protein acidic and rich in cysteine (SPARC) PMID 40588098. It is a multifunctional protein that acts as a pleiotropic regulator across several anatomical systems PMID 40588098.
", "biologicalFunction": "FSTL1 is considered an exerkine because its expression and secretion are dynamically regulated by physical activity PMID 40588098:
\nCardiovascular Disease: FSTL1 shows cardioprotective effects in myocardial infarction. Administration of FSTL1 protein significantly reduced infarct size in both mouse and pig models of ischemia/reperfusion injury by inhibiting apoptosis and inflammatory responses through AMP-activated protein kinase and bone morphogenetic protein-4 pathways PMID 22929303. FSTL1 orchestrates post-infarction healing through multiple signaling cascades including BMP/SMAD, PI3K/AKT, MAPK, and TGF-β pathways, coordinating inflammation resolution, extracellular matrix remodeling, and functional recovery PMID 41602834, Additionally, FSTL1 protects against hypoxia-induced pulmonary hypertension by suppressing pulmonary artery smooth muscle cell proliferation and migration via the ERK signaling pathway PMID 28361925.
\nFibrotic Diseases: Epitope-specific monoclonal neutralizing antibodies targeting FSTL1 demonstrated potent antifibrotic effects in preclinical models. FSTL1 neutralizing antibodies attenuated bleomycin-induced pulmonary and dermal fibrosis, reduced TGF-β1-induced dermal fibrosis in human skin ex vivo, and significantly reduced existing lung and skin fibrosis PMID 33007201. These antibodies exerted their effects by reducing TGF-β1 responsiveness and subsequent myofibroblast activation PMID 33007201.
\nInflammatory and Autoimmune Diseases: FSTL1 neutralizing antibodies attenuated collagen-induced arthritis severity in mice with reduced inflammatory responses PMID 33007201. However, FSTL1's role in inflammation appears context-dependent, as it has been identified as a proinflammatory protein that enhances synthesis of proinflammatory cytokines and chemokines PMID 24838142.
\nRenal Disease: FSTL1 plays a role in kidney pathology, particularly in renal fibrosis, inflammation, and ischemia-reperfusion injury, suggesting potential as both a biomarker and therapeutic target PMID 40239460.
" }, "pmids": [ "22929303", "24838142", "28361925", "33007201", "38107476", "38786764", "40210118", "40239460", "40588098", "40818821", "41602834" ] }, { "id": "ela", "shortName": "ELA", "fullName": "ELABELA (ELA)", "tier": 3, "sourceTissue": "Kidney (nephrokine)", "moleculeType": "Peptide", "keyPathway": "APJ (apelin receptor); Akt, SIRT3", "domains": { "cv": "primary", "met": null, "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": ", also known as apela, is a newly identified signaling molecule that acts as a novel endogenous ligand for the apelin receptor (APJ) PMID 40588098PMID 40210118.
", "biologicalFunction": "Note: text from PMID 40210118 about ELA: Exercise has been demonstrated to promote the secretion of exerkines by the kidney. These exerkines regulate the function of the cardiovascular system through blood circulation. A new study found that ELABELA (ELA), a novel endogenous ligand for the apelin receptor (APJ), is mainly secreted by the kidney in mice. Exercise-stimulated increase in kidney secretion of ELA ameliorates myocardial injury . In myocardial infarction and cardiac I/R injury, tail vein injections of ELA in mice promoted angiogenesis, reduced cardiac fibrosis, and improved cardiac function [37]. ELA treatment significantly decreases diastolic blood pressure, reduces vascular inflammation and oxidative stress in hypertensive rats [38], and inhibits pressure overload-induced HF [39]. The interaction between the heart and kidney is mediated by exerkine endocytosis. As an exerkine derived from the kidney, ELA plays a role in regulating the kidney and cardiovascular systems through humoral mechanisms. This may represent a novel target for the treatment of cardiovascular diseases.
\nELABELA (ELA) demonstrates therapeutic potential across multiple cardiovascular, renal, and neurological conditions, with evidence supporting its use in hypertension, heart failure, acute kidney injury, ischemic stroke, and pulmonary arterial hypertension. PMID 32740407PMID 36029072PMID 28137936PMID 33290073PMID 37433415
\nELA functions as an endogenous ligand for the APJ receptor and exhibits vasodilatory, cardioprotective, and renoprotective effects when administered peripherally. PMID 32740407PMID 29350399 In pulmonary arterial hypertension, exogenous ELA administration significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in rat models. PMID 28137936 For acute kidney injury, modified ELA analogues (PEGylated and acylated forms) showed enhanced receptor binding, prolonged stability, and protective effects against ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. PMID 33290073
\nELA also demonstrates neuroprotective properties by inhibiting neuronal ferroptosis in cerebral ischemia/reperfusion injury, reducing brain infarction and improving neurobehavioral outcomes through activation of the NRF2/ARE antioxidative signaling pathway. PMID 36681202 In sepsis-induced myocardial dysfunction, the ELA-APJ axis reduced pyroptosis by promoting autophagy and decreasing oxidative stress. PMID 39241986
\nThe primary limitation for clinical application is ELA's short half-life and requirement for parenteral administration. PMID 32740407 To address this, modified formulations including PEG-ELA-21, Fc-ELA-21, albumin-ELA-21, and acylated analogues have been developed with improved stability and efficacy. PMID 32740407PMID 33290073 These modifications enhance receptor binding capacity and plasma stability while maintaining therapeutic effects.
\nCirculating ELA levels may serve as a diagnostic biomarker for various cardiovascular diseases, as ELA expression is downregulated in conditions like pulmonary arterial hypertension, heart failure, and preeclampsia. PMID 37776977PMID 28137936PMID 37433415
" }, "pmids": [ "28137936", "29350399", "32740407", "33290073", "36029072", "36681202", "37433415", "37776977", "39241986", "39988270", "40210118", "40588098" ] }, { "id": "fractalkine", "shortName": "Fractalkine", "fullName": "Fractalkine (CX3CL1)", "tier": 3, "sourceTissue": "Skeletal muscle; endothelial cells; neurons", "moleculeType": "Chemokine", "keyPathway": "CX3CR1; ERK, NF-κB", "domains": { "cv": null, "met": null, "neuro": null, "msk": null, "inflam": "primary", "onco": null }, "sections": { "definition": "Fractalkine (CX3CL1) is a unique immunologic protein and member of the chemokine family that exists in both membrane-bound and secreted forms and is primarily expressed by skeletal muscle cells, vascular endothelial cells, neurons, and adipocytes PMID 37395284PMID 40943107.
", "biologicalFunction": "From PMID 40943107): In addition, fractalkine has been described to be modulated in response to exercise and is thus considered as an exerkine [8,150]. Lee, Y.S. et al. have demonstrated a positive effect of fractalkine on glucose stimulated insulin secretion (+58%) but preferentially mediated by an indirect mediator rather than acting as an insulin secretagogue [151]. These results are in accordance with those from Rutti et al. who have also demonstrated a protective role for the exerkine in Beta cells [152]. Fractalkine is expressed by a wide range of cell types such as endothelial cells or neurons in a physiological state and has also been described to be secreted by adipocytes [153]. Its first role was attributed to neuroprotective functions after brain injuries. As a chemokine, fractalkine is also considered an adhesion molecule in charge of cell immunity recruitment. In a pathological context, fractalkine can also be implicated in more adverse effects [154]. The chemokine is also involved in metabolic processes. Fractalkine knockout mice exhibit an impaired glucose tolerance while fractalkine administration has been reported to restore glycemia by enhancing insulin secretion [151]. It has been reported that fractalkine levels were elevated in patients with T2D compared with a control group [153,155] and is associated with inflammation [156]. Thus, once again, depending on the secretory context, secreted molecules can reveal a dual facet. Physical exercise could thus beneficially alter their functions for greater impact, notably mediated for Beta cell health improvement
", "exerkineClassification": "Fractalkine is classified as an exerkine because its expression and circulating levels are dynamically regulated by physical activity:
\nFractalkine (CX3CL1) and its receptor CX3CR1 have substantial therapeutic potential across multiple disease categories, including neurodegenerative diseases, cancer, inflammatory disorders, and pain syndromes.
\nNeurodegenerative Diseases: The CX3CL1/CX3CR1 axis represents a promising therapeutic target for modulating neuroinflammation in conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. [1-3, PMID 34492237PMID 30496784PMID 26927660] CX3CL1 predominantly functions to reduce proinflammatory responses and exerts neuroprotective effects by regulating microglial activation. [1, 4, PMID 34492237PMID 39940727] In brain ischemia, CX3CL1 protects by modulating microglial phenotype and metabolism, inhibiting microglial activation while increasing anti-inflammatory gene expression. [5, PMID 31607865] For diabetic retinopathy specifically, fractalkine appears to mitigate inflammation, oxidative stress, and neuronal damage in early-stage disease. [6, PMID 39796231]
\nCancer: The therapeutic potential in oncology is complex and context-dependent. CX3CL1 can recruit antitumor immune cells (NK cells, cytotoxic T cells) into the tumor microenvironment, and increased tumor CX3CL1 levels correlate with improved prognosis in colorectal, breast, and lung cancers. [7-8, PMID 32060841PMID 32466280] However, CX3CL1 also demonstrates protumorigenic effects in certain malignancies by promoting angiogenesis, metastasis, and interactions with tumor-associated macrophages. [9-11, PMID 39125578PMID 38731899PMID 35770395]
\nInflammatory and Rheumatic Diseases: Fractalkine shows therapeutic promise in rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and scleroderma. [12, PMID 22566871] The axis also plays important roles in cardiovascular disease, atherosclerosis, glomerulonephritis, and osteoarthritis. [13-15, PMID 12969992PMID 20055718PMID 24556958]
\nPain Management: The CX3CL1/CX3CR1 pathway represents a major target for treating neuropathic and spinal cord pain. [1, 14, 16, PMID 34492237PMID 20055718PMID 22530606] Despite this extensive preclinical evidence, no therapeutics targeting fractalkine or CX3CR1 have entered clinical use to date. [14, 16, PMID 20055718PMID 22530606]
" }, "pmids": [ "12969992", "20055718", "22530606", "22566871", "24556958", "26927660", "30496784", "31607865", "32060841", "32466280", "34492237", "35304603", "35770395", "37395284", "38107476", "38393277", "38731899", "39125578", "39136551", "39796231", "39940727", "40801027", "40818821", "40943107" ] }, { "id": "omentin", "shortName": "Omentin", "fullName": "Omentin", "tier": 3, "sourceTissue": "Visceral adipose (adipokine)", "moleculeType": "Glycoprotein", "keyPathway": "PI3K/AKT; AMPK/PGC1α", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Omentin (specifically Omentin-1) is an exercise-induced adipokine that is primarily expressed in and secreted by visceral adipose tissue into the circulation PMID 40210118PMID 37730552.
", "biologicalFunction": "From PMID 40210118: Omentin is expressed in visceral adipose tissue, and exercise increases Omentin levels in vivo [43]. The overexpression of Omentin in adipose tissue has been demonstrated to reduce the area affected by myocardial infarction and inhibit cardiomyocyte apoptosis [44]. Omentin mitigates high glucose-induced vascular endothelial dysfunction by inhibiting endoplasmic reticulum stress (ERS) and oxidative stress [45]. In addition, Omentin reduces arterial calcification. It is expected to be a novel target for the treatment of cardiovascular disease
", "therapeuticPotential": "Omentin-1 has demonstrated therapeutic potential in several disease states. In heart failure with preserved ejection fraction (HFpEF), omentin-1 experimentally alleviates myocardial ischemic injury, cardiac hypertrophy, and reduces oxidative and endoplasmic reticulum stress in endothelial cells while promoting nitric oxide-mediated vasodilation. PMID 40886173 Clinically, circulating omentin-1 levels are decreased in patients with HFpEF and inversely related to inflammatory biomarkers, with levels increasing following GLP-1 receptor agonist treatment. PMID 40886173
\nFor type 2 diabetes and vascular complications, omentin-1 treatment ameliorates endothelial dysfunction by reducing vascular superoxide production, improving nitric oxide bioavailability, and restoring the anti-contractile action of perivascular adipose tissue. PMID 33099000 It protects against high glucose-induced endothelial dysfunction through the AMPK/PPARδ signaling pathway by inhibiting endoplasmic reticulum stress and oxidative stress. PMID 32001235 Recent evidence shows omentin-1 promotes wound healing in diabetic mice by enhancing vascular endothelial cell function through the PI3K/AKT/FOXO1 pathway. PMID 41266618
\nIn metabolic dysfunction-associated steatotic liver disease (MASLD), omentin-1 supplementation reduces TNF-α levels, endoplasmic reticulum stress, and oxidative stress in hepatocytes, likely through inhibition of NF-κB and MAPK signaling pathways. PMID 38082368 For atherosclerosis and ischemic stroke, omentin-1 exhibits anti-atherosclerotic properties and may serve as a therapeutic target, with metformin and statins shown to elevate omentin-1 levels. PMID 33607071
\nAdipose tissue inflammation in obesity is attenuated by omentin-1 through restoration of TXNIP/NLRP3 signaling, improving glucose tolerance and insulin sensitivity. PMID 32479684 The adipokine also demonstrates anti-inflammatory effects in macrophages by inhibiting the TLR4/MyD88/NF-κB signaling pathway. PMID 31706880
\nTherapeutic strategies to increase omentin-1 levels include weight loss, olive oil-rich diet, aerobic training, and treatment with atorvastatin and antidiabetic drugs (metformin, pioglitazone, and exenatide). PMID 28640441 These findings collectively support omentin-1 as a promising therapeutic target for metabolic and cardiovascular diseases. PMID 35107051PMID 22724476
" }, "pmids": [ "22724476", "28640441", "31706880", "32001235", "32479684", "33099000", "33607071", "35107051", "36351545", "37730552", "38082368", "38786764", "40210118", "40886173", "41266618" ] }, { "id": "apelin", "shortName": "Apelin", "fullName": "Apelin", "tier": 3, "sourceTissue": "Adipose (adipokine); multi-tissue", "moleculeType": "Peptide", "keyPathway": "APJ (APLNR); Gi/Gq signaling", "domains": { "cv": "primary", "met": null, "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Apelin is an endogenous peptide ligand of the G-protein-coupled receptor APJ (also known as AGTRL1 or APLNR), encoded by the APLN gene and existing in multiple active isoforms including apelin-36, -17, -13, and pyroglutamated apelin-13. PMID 38089606PMID 29875677PMID 21725702 Apelin is classified as an adipokine because it is produced and secreted by adipocytes, though it is also widely expressed in cardiovascular, nervous, renal, and other tissues. PMID 29875677PMID 21725702
", "biologicalFunction": "of apelin are diverse and include regulation of cardiovascular physiology (positive inotropic effects, vasodilation, blood pressure control), angiogenesis, energy metabolism, fluid homeostasis, cell proliferation, and apoptosis. PMID 29875677PMID 33679444PMID 36611944 Apelin improves glucose and lipid metabolism, promotes mitochondrial oxidation and biogenesis, and mitigates oxidative stress and inflammatory pathways. PMID 40886173 In the cardiovascular system specifically, apelin enhances cardiac contractility, increases stroke volume, promotes diuresis, and exerts cardioprotective effects by reducing maladaptive hypertrophy, inflammation, and fibrosis. PMID 40886173PMID 36523134PMID 41155377
", "exerkineClassification": "(exercise-sensitive factor) because its expression and secretion are regulated by various forms of exercise. PMID 38089606 The classification as an exerkine is supported by evidence that apelin responds to physical activity and may mediate some of the beneficial metabolic effects of exercise, particularly in the context of metabolic disease prevention and treatment. PMID 38089606 This exercise-responsive characteristic, combined with its role in energy metabolism and its secretion by adipose tissue, positions apelin as both an adipokine and an exerkine that links physical activity to metabolic health outcomes.
", "therapeuticPotential": "The apelinergic system shows promise for treating heart failure, pulmonary arterial hypertension, and coronary artery disease. PMID 34801627PMID 31236974PMID 27825851 Apelin exerts positive inotropic effects in both healthy and failing hearts, promotes vasodilation, and mitigates maladaptive cardiac hypertrophy, inflammation, and fibrosis. PMID 40886173PMID 27825851 In heart failure with reduced ejection fraction (HFrEF), serum apelin levels are decreased and have adverse prognostic significance. PMID 40886173 The peptide also demonstrates cardioprotective effects against ischemia/reperfusion injury and post-ischemic remodeling. PMID 30659278
\nMetabolic and Renal Disorders. Apelin demonstrates anti-diabetic and anti-obesity properties through improved glucose and lipid metabolism, enhanced mitochondrial oxidation, and promotion of brown adipogenesis. PMID 40886173PMID 26007641PMID 33838166 The system also shows therapeutic potential for insulin resistance, hyponatremia, and preeclampsia. PMID 34801627PMID 31236974 Apelin decreases epithelial sodium channel activity and inhibits vasopressin actions on renal collecting tubules, promoting diuresis. PMID 40886173
\nHypertension. Systemic administration of apelin-13 or its modified form (pyroglutamate apelin-13) exerts vasodilatory and antihypertensive effects. PMID 27258138 The peptide antagonizes the renin-angiotensin system by promoting ACE2 transcription and antagonizing angiotensin II effects. PMID 32901821
\nTherapeutic Challenges. A major limitation is that native apelin peptides are rapidly degraded by endogenous peptidases including ACE2, neprilysin, and kallikrein. PMID 34801627PMID 32901821 This has driven development of metabolically stable apelin analogs and synthetic non-peptide APJ receptor agonists as more viable therapeutic alternatives. PMID 34801627PMID 31236974PMID 27825851
" }, "pmids": [ "21725702", "26007641", "27258138", "27825851", "29875677", "30659278", "31236974", "32901821", "33679444", "33838166", "34801627", "36523134", "36611944", "38089606", "40886173", "41155377" ] }, { "id": "adiponectin", "shortName": "Adiponectin", "fullName": "Adiponectin", "tier": 3, "sourceTissue": "White adipose (adipokine)", "moleculeType": "Adipokine", "keyPathway": "AdipoR1/R2; AMPK, PPARα", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Adiponectin is an adipocyte-derived hormone that circulates at high concentrations (approximately 3-6 orders of magnitude greater than typical hormones) and serves as a key regulator of glucose and lipid metabolism. PMID 29978896PMID 31731079 It is secreted primarily by white adipose tissue, though cardiomyocytes, endothelial cells, and skeletal muscle cells also produce it. PMID 35890325
", "biologicalFunction": "Biological functions include enhancing insulin sensitivity by stimulating fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. PMID 29978896PMID 26993047 Adiponectin activates AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPARα) pathways through its receptors AdipoR1 and AdipoR2. PMID 29978896 Beyond metabolic effects, adiponectin exhibits anti-inflammatory, anti-apoptotic, and cardioprotective properties by reducing vascular inflammation, inhibiting endothelial adhesion molecule expression, and decreasing oxidative stress. PMID 29978896PMID 22796520 Uniquely among adipokines, circulating adiponectin levels are inversely correlated with body fat mass despite being produced by adipocytes. PMID 31731079PMID 35196429
", "exerkineClassification": "Adiponectin is considered an exerkine. Exercise increases adiponectin levels in rodents, enhancing fatty acid oxidation and glucose uptake in skeletal muscle. PMID 40157803 In humans, chronic exercise training increases adiponectin receptor expression, which may mediate improvements in insulin resistance following exercise. PMID 25126860 Adiponectin crosses the blood-brain barrier where it modulates hippocampal neurogenesis, mood regulation, and stimulates anti-inflammatory cytokine release. PMID 40157803 These exercise-responsive properties—increased secretion with physical activity, systemic circulation to distant tissues, and beneficial metabolic effects—support its classification as an exerkine, though it functions as an adipokine under baseline conditions. PMID 40157803PMID 22876920
\nHuman studies show that exercise interventions can modulate circulating adiponectin levels, particularly when combined with dietary modifications. PMID 22876920
", "therapeuticPotential": "Adiponectin represents a therapeutic target for metabolic and cardiovascular diseases based on its insulin-sensitizing, anti-inflammatory, and cardioprotective properties. PMID 23448486PMID 24957699 Therapeutic strategies include direct replacement and indirect upregulation approaches, though clinical translation remains limited. PMID 25818192
\nDirect approaches include recombinant adiponectin administration, gene transfer, synthetic peptide mimetics, and adiponectin receptor agonists (e.g., AdipoRon). PMID 23448486PMID 22876919PMID 25818192 Receptor agonists bypass the need for full-length protein and demonstrate favorable effects in preclinical HFpEF models. PMID 22876919PMID 40886173 However, complex oligomeric structure, short half-life, and delivery challenges limit protein-based approaches. PMID 25818192PMID 22876919
\nIndirect pharmacological strategies to increase endogenous adiponectin include thiazolidinediones (PPARγ agonists), which exert insulin-sensitizing effects predominantly through adiponectin upregulation, though cardiovascular and bone safety concerns limit use. PMID 34181914PMID 25818192PMID 12611609 Fibric acid derivatives, RAAS blockers, and certain statins show modest adiponectin-elevating effects. PMID 24957699PMID 25818192PMID 24603219
\nLifestyle interventions including weight loss, Mediterranean diet, omega-3 supplementation, and regular exercise reliably modulate adiponectin levels or receptor expression. PMID 26764331PMID 24603219PMID 22257055
\nDespite compelling preclinical evidence demonstrating metabolic correction and cardioprotection in animal models, PMID 23448486PMID 40886173PMID 19906806 no adiponectin-based therapeutic has achieved regulatory approval. Thiazolidinediones and lifestyle modifications remain the only evidence-based approaches to therapeutically modulate the adiponectin system in humans. PMID 25818192
" }, "pmids": [ "12611609", "19906806", "22257055", "22796520", "22876919", "22876920", "23448486", "24603219", "24957699", "25126860", "25818192", "26764331", "26993047", "29978896", "31731079", "34181914", "35196429", "35890325", "40157803", "40886173" ] }, { "id": "decorin", "shortName": "Decorin", "fullName": "Decorin", "tier": 3, "sourceTissue": "Skeletal muscle; ECM", "moleculeType": "Proteoglycan (SLRP)", "keyPathway": "Pan-RTK inhibitor; TGF-β binding", "domains": { "cv": null, "met": null, "neuro": null, "msk": "primary", "inflam": null, "onco": null }, "sections": { "definition": "Decorin is a small leucine-rich proteoglycan (SLRP) that functions both as a structural component of the extracellular matrix (ECM) and as a signaling molecule. PMID 29435195 It consists of a protein core composed of leucine-rich repeats with a dermatan sulfate glycosaminoglycan side chain attached at its N-terminus. PMID 22877511PMID 32354384
", "biologicalFunction": "Decorin's primary structural role involves regulating collagen fibrillogenesis by binding to collagen fibrils, ensuring they are uniformly sized and regularly spaced—particularly critical for corneal transparency. PMID 21342131 Beyond this matrix-organizing function, decorin acts as a multifunctional signaling molecule through several mechanisms:
\nGrowth factor modulation: Decorin binds and sequesters transforming growth factor-beta (TGF-β), a key regulator of fibrosis, thereby exerting potent anti-fibrotic effects PMID 29435195PMID 40279258PMID 21342131
\nReceptor tyrosine kinase (RTK) inhibition: It functions as a pan-RTK inhibitor, binding to and downregulating multiple receptors including EGFR, HER2, Met, VEGFR2, and IGF-R, leading to growth suppression and anti-tumorigenic effects PMID 35171698PMID 22735579PMID 18798267
\nAnti-angiogenic activity: Through VEGFR2 interaction, decorin inhibits angiogenesis and induces endothelial cell autophagy PMID 26522384
", "exerkineClassification": "Decorin is considered a myokine (a type of exerkine). Decorin is released from contracting skeletal muscle and its circulating levels increase in response to acute resistance exercise in humans. PMID 24996176 Furthermore, decorin expression in skeletal muscle increases after chronic training in both humans and mice. PMID 24996176
\nThis myokine function positions decorin as a mediator of exercise's beneficial effects on muscle remodeling and potentially systemic health outcomes.
", "therapeuticPotential": "Decorin functions as a pan-receptor tyrosine kinase inhibitor and has shown oncosuppressive effects by binding to multiple receptor tyrosine kinases (EGFR, HER2, Met, VEGFR2, IGFR) and inhibiting downstream signaling pathways that promote tumor growth, angiogenesis, and metastasis. PMID 26522384PMID 35171698PMID 39954173 Studies indicate decorin suppresses tumorigenic growth and prevents metastatic lesions in various in vitro and in vivo tumor models. PMID 26522384PMID 26697491PMID 18798267
\nAs an antifibrotic agent, decorin primarily inhibits transforming growth factor-β (TGF-β), a major driver of fibrosis in multiple organs including heart, liver, skin, and muscle. PMID 40279258 Therapeutic applications using recombinant protein, gene-delivery systems, and decorin-loaded hydrogels have demonstrated potential for both localized and systemic fibrosis treatment. PMID 40279258 Decorin has shown efficacy in preventing epidural fibrosis and adhesions after laminectomy by suppressing TGF-β1-induced fibroblast proliferation and extracellular matrix production via the Smad2/3 signaling pathway. PMID 34975478
\nIn cardiovascular disease, decorin improves cardiac function following myocardial infarction through anti-inflammatory and anti-apoptotic effects, with studies showing improved cardiac hemodynamics, reduced oxidative stress, and decreased expression of inflammatory markers (TNF-α, IL-1β, TGF-β1). PMID 36917819
\nDecorin also plays a role in autoimmune and inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, and multiple sclerosis, through immune regulation mechanisms. PMID 36033387
" }, "pmids": [ "18798267", "21342131", "22735579", "22877511", "24996176", "26522384", "26697491", "29435195", "32354384", "34975478", "35171698", "36033387", "36917819", "39954173", "40279258" ] }, { "id": "kyna", "shortName": "KYNA", "fullName": "Kynurenic Acid (KYNA)", "tier": 3, "sourceTissue": "Skeletal muscle (KAT-mediated)", "moleculeType": "Metabolite", "keyPathway": "NMDA antagonist; GPR35", "domains": { "cv": null, "met": null, "neuro": "primary", "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Kynurenic acid (KYNA) is a neuroprotective metabolite produced in skeletal muscle during exercise when PGC-1α upregulates kynurenine aminotransferases (KATs) to convert circulating kynurenine into KYNA, a compound that—unlike its precursor—cannot readily cross the blood–brain barrier PMID 40818821PMID 39456173PMID 38249295. By sequestering kynurenine peripherally and antagonizing NMDA receptors, KYNA can mediate resilience to stress-induced depression PMID 40869331PMID 39456173PMID 38393277PMID 38249295. It also promotes adipose tissue browning via GPR35 signaling PMID 40869331.
", "biologicalFunction": "KYNA is classified as an exerkine (specifically a myokine) because physical activity directly regulates the enzymes responsible for its production, altering its systemic levels to benefit multiple organs.
\n1. Neurological and Psychiatric Disorders
\n2. Inflammatory and Immune-Mediated Diseases
\n3. Gastrointestinal and Metabolic Health
\n4. Oncology
\nClusterin (CLU) is an exercise-induced hepatokine and extracellular chaperone that suppresses neuroinflammation by inhibiting the complement cascade in brain endothelial cells and facilitates the clearance of pathogenic proteins like amyloid-β and α-synuclein PMID 40818821PMID 39818278PMID 38249295. As a critical mediator of the benefits of exercise on the brain, elevated circulating CLU levels are essential for the transfer of neuroprotective effects with studies showing that its depletion abolishes the cognitive improvements typically conferred by physical activity PMID 38393277PMID 38249295.
", "biologicalFunction": "Clusterin is classified as an exerkine (primarily a hepatokine, though also expressed in muscle) because its circulating levels are modulated by physical activity, and it has been identified as a necessary mediator of exercise-induced neuroprotection.
\n1. Neurological Disorders and Brain Injury
\n2. Oncology: Resistance and Progression
\n3. Cardiovascular and Metabolic Diseases
\n4. Other Therapeutic Applications
\nHSP72 (Heat Shock Protein 72) is a member of the heat shock protein family that serves as a bioactive signaling molecule, or exerkine, primarily released from the hepatosplanchnic circulation and skeletal muscle into the bloodstream in response to physical activity PMID 39136551PMID 39818278.
", "biologicalFunction": "Stress Response:
\nCardiovascular protection represents a major therapeutic application. HSP72 administration has shown cardioprotective effects in ischemia-reperfusion injury through multiple mechanisms, including inhibition of apoptotic pathways (apoptosome, apoptosis-inducing factor, and nuclear factor-κB pathways) and facilitation of protein folding and chaperoning. PMID 28911512 A fusion construct (Fv-HSP72) combining HSP72 with a cell-penetrating antibody fragment has been validated in cerebral infarction models and is being tested clinically for ischemic events. PMID 27152638
\nHepatoprotection has been demonstrated in transgenic mice overexpressing HSP72, which showed reduced liver injury from acetaminophen toxicity, methionine choline-deficient diet, and other hepatotoxic insults through attenuation of hepatocellular death, oxidative stress, and JNK signaling. PMID 29331340 HSP72 levels are elevated in patients with non-alcoholic steatohepatitis and chronic hepatitis C, correlating with hepatic inflammation severity. PMID 29331340
\nNeuroprotection occurs through inhibition of the JNK3 signaling pathway via Akt1 activation during cerebral ischemia, reducing neuronal death in hippocampal regions. PMID 22386689 HSP72 regulates both apoptotic and inflammatory signaling in cerebral ischemia, with net prosurvival effects. PMID 18648242
\nAnti-inflammatory effects involve inhibition of HMGB1 release and proinflammatory function in macrophages, interfering with the CRM1-dependent nuclear export pathway and suppressing MAP kinase and NF-κB pathways. PMID 17617616
\nMetabolic applications include potential therapeutic roles in obesity and type 2 diabetes, where HSP72 manipulation may improve glucose homeostasis by addressing inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction. PMID 25379403
\nHSP72 has also been investigated for pulmonary cytoprotection as a medical countermeasure for inhalation toxicants and for maintaining protein homeostasis under heat stress through regulation of misfolded protein metabolism via autophagy pathways. PMID 27152638PMID 41306019
\nHuman studies show more variable results compared to animal models, with some reporting protective effects while others suggest possible associations with mortality or infections in sepsis. PMID 24524071
" }, "pmids": [ "17617616", "18648242", "22386689", "24524071", "25379403", "27152638", "28911512", "29331340", "35304603", "39136551", "39335489", "39818278", "39852400", "41306019" ] }, { "id": "baiba", "shortName": "BAIBA", "fullName": "β-Aminoisobutyric Acid (BAIBA)", "tier": 3, "sourceTissue": "Skeletal muscle (myokine/metabolite)", "moleculeType": "Metabolite", "keyPathway": "AMPK; PPARα; MRGPRD (bone)", "domains": { "cv": null, "met": "primary", "neuro": null, "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Beta-aminoisobutyric acid (BAIBA) is a small molecule metabolite produced primarily from the catabolism of valine and thymine in skeletal muscle. PMID 37313446 It exists as two enantiomers (R-BAIBA and S-BAIBA), with R-BAIBA being approximately 67 times more abundant in human plasma than S-BAIBA. PMID 31611815
", "biologicalFunction": "BAIBA functions as a signaling metabolite with multiple biological effects, including regulation of lipid and glucose metabolism, promotion of white adipose tissue browning, enhancement of hepatic fatty acid oxidation, anti-inflammatory properties, and protection against oxidative stress. PMID 37313446PMID 24411942 It acts through several mechanisms, including activation of AMPK signaling and PPARα-mediated pathways. PMID 24411942PMID 31277947PMID 38219388 BAIBA also demonstrates protective effects on bone by preventing osteocyte apoptosis through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD). PMID 29425508
", "exerkineClassification": "BAIBA is considered an exerkine (also termed a myokine). PMID 37313446PMID 38219388PMID 29177585PMID 40157803 This classification is supported by several lines of evidence:
\nThe molecule has been described as a potential \"exercise pill\" due to its ability to confer metabolic benefits similar to those of exercise. PMID 37313446
", "therapeuticPotential": "BAIBA has shown therapeutic effects in type 2 diabetes and metabolic disorders. In diabetic mice, oral BAIBA administration reduced blood glucose and lipid levels, attenuated hepatic insulin resistance and lipid accumulation, and reduced hepatic endoplasmic reticulum stress and apoptosis through AMPK-dependent mechanisms. PMID 26907958 These metabolic benefits extend to adipose tissue, where BAIBA attenuated LPS-induced inflammation and insulin resistance in adipocytes, also via AMPK-mediated pathways. PMID 29592806
\nThe compound has been characterized as a signaling metabolite and potential \"exercise pill\" due to its production during exercise and involvement in regulating lipid, glucose, and bone metabolism, as well as inflammation and oxidative stress. PMID 37313446 BAIBA enhances fatty acid oxidation and reduces body weight through increased leptin production by white adipose tissue. PMID 19735301
\nSafety data support its therapeutic development. A 90-day subchronic toxicity study in rats established a no-observed-adverse-effect level (NOAEL) of 900 mg/kg/day, with no treatment-related adverse effects observed. PMID 35549583
\nAdditional therapeutic applications have been explored in neuropsychiatric conditions. BAIBA functions as a gliotransmitter that activates GABA-B and group-III metabotropic glutamate receptors, potentially contributing to clozapine's efficacy in treatment-resistant schizophrenia. PMID 37759688
\nBAIBA has also been investigated as a biomarker in malignancy, with elevated urinary concentrations found in patients with leukemia and non-Hodgkin lymphoma, though this represents diagnostic rather than therapeutic utility. PMID 3652458
\nHuman studies and reviews have identified BAIBA-related metabolites as part of metabolic pathways associated with type 2 diabetes development, further supporting its relevance in metabolic disease therapeutics. PMID 34325838
" }, "pmids": [ "19735301", "24411942", "26907958", "28441626", "29177585", "29425508", "29592806", "31277947", "31611815", "34325838", "35549583", "3652458", "37313446", "37759688", "38219388", "40157803" ] }, { "id": "myonectin", "shortName": "Myonectin", "fullName": "Myonectin (CTRP15)", "tier": 4, "sourceTissue": "Skeletal muscle (myokine)", "moleculeType": "Secreted protein (C1q/TNF family)", "keyPathway": "S1P/cAMP/Akt; AMPK/PGC1α", "domains": { "cv": null, "met": null, "neuro": null, "msk": "primary", "inflam": null, "onco": null }, "sections": { "definition": "Myonectin (also known as CTRP15 or erythroferrone) is a secreted protein predominantly produced by skeletal muscle that functions as a myokine regulating systemic lipid metabolism, mitochondrial function, and tissue protection. The molecule belongs to the C1q/TNF-related protein (CTRP) family and forms disulfide-linked oligomers (trimers, hexamers, and higher-order structures) that are critical for its biological activity. PMID 22351773PMID 40741175PMID 32602701
", "biologicalFunction": "Myonectin's primary biological functions include promoting fatty acid uptake in adipocytes and hepatocytes, reducing circulating free fatty acids, and protecting against ischemia-reperfusion injury in the heart. It upregulates genes involved in lipid uptake (CD36, FATP1, Fabp1, Fabp4) and activates key signaling pathways including sphingosine-1-phosphate (S1P)/cAMP/Akt and AMPK/PGC1α cascades. PMID 30566056PMID 22351773PMID 37542026 These pathways mediate anti-apoptotic, anti-inflammatory, and mitochondrial biogenesis effects across multiple tissues. PMID 30566056PMID 40741175PMID 37542026
", "exerkineClassification": "Myonectin is considered an exerkine—specifically an exercise-induced myokine. This classification is supported by several lines of evidence: (1) voluntary exercise increases both its skeletal muscle expression and circulating levels; (2) treadmill exercise elevates circulating myonectin, and this elevation is necessary for exercise-mediated cardioprotection against ischemia-reperfusion injury; (3) myonectin is upregulated by compounds that raise cellular cAMP or calcium levels, mimicking exercise-induced muscle contraction; and (4) it is recognized in recent reviews as a canonical myokine that mediates inter-organ crosstalk in response to exercise. PMID 30566056PMID 31442362PMID 22351773PMID 40957493
\nMyonectin expression is tightly regulated by metabolic state—fasting suppresses while refeeding dramatically increases its levels—and it is downregulated in obesity. PMID 22351773PMID 40741175
", "therapeuticPotential": "Myonectin shows promise as a therapeutic target for skeletal muscle atrophy and dysfunction. In male mouse models, myonectin supplementation attenuated denervation-induced muscle atrophy through AMPK/PGC1α pathway activation, and treatment suppressed muscle atrophy in both senescence-accelerated mice and mdx mice (a model of Duchenne muscular dystrophy). PMID 37542026 These findings suggest potential applications in age-related sarcopenia and muscular dystrophies.
\nCardiovascular protection represents another therapeutic avenue. Myonectin functions as an exercise-induced myokine that protects against myocardial ischemia-reperfusion injury by suppressing apoptosis and inflammation through S1P/cAMP/Akt-dependent signaling. PMID 30566056 Transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion in mice. PMID 30566056
\nThe myokine also demonstrates metabolic regulatory potential. Myonectin regulates lipid uptake and distribution across tissues, reduces inflammation and apoptosis, and modulates mitochondrial function through AKT and AMPK-mediated pathways. PMID 40741175 It promotes fatty acid uptake in adipocytes and hepatocytes while reducing circulating free fatty acids, and inhibits adipogenesis through p38 MAPK pathway regulation. PMID 22351773PMID 33407993
\nClinical biomarker applications are supported by human studies showing decreased myonectin levels in type 2 diabetes, obesity, and metabolic syndrome. PMID 29161407PMID 31340393PMID 37108038PMID 37782189 Lower levels correlate with poor glycemic control and metabolic parameters, suggesting myonectin could serve both as a predictive marker and potential therapeutic target for metabolic diseases. PMID 37782189PMID 40741175PMID 29161407PMID 31340393
" }, "pmids": [ "22351773", "29161407", "30566056", "31340393", "31442362", "32602701", "33407993", "37108038", "37542026", "37782189", "40741175", "40957493" ] }, { "id": "lubricin", "shortName": "Lubricin", "fullName": "Lubricin (PRG4)", "tier": 4, "sourceTissue": "Synovial joint", "moleculeType": "Glycoprotein", "keyPathway": "TLR2/4 antagonist", "domains": { "cv": null, "met": null, "neuro": null, "msk": "primary", "inflam": null, "onco": null }, "sections": { "definition": "Lubricin (also known as proteoglycan 4 or PRG4) is a surface-active mucinous glycoprotein that serves as the primary boundary lubricant in synovial joints. It is encoded by the PRG4 gene and secreted by superficial zone cells of articular cartilage and synoviocytes.
", "biologicalFunction": "Lubricin provides boundary lubrication by coating the cartilage surface, enabling near-frictionless joint motion and preventing cell and protein adhesion. Its lubricating function depends critically on extensive O-linked glycosylation within its mucin-rich domain. Beyond lubrication, lubricin plays multiple protective roles: it prevents chondrocyte apoptosis in superficial cartilage layers, modulates superficial zone cell differentiation to maintain cartilage homeostasis, and regulates inflammatory responses by binding to and antagonizing Toll-like receptors 2 and 4. The protein also interacts with cartilage matrix proteins including COMP, fibronectin, and collagen II to anchor itself to the cartilage surface, and forms crosslinks with galectin-3 that reinforce the lubricating boundary layer.
", "exerkineClassification": "Lubricin is considered an exerkine, as its expression increases with joint movement and exercise. The evidence supporting this classification includes the observation that lubricin synthesis is triggered by mechanical loading and joint motion. In the context of osteoarthritis prevention and treatment, lubricin functions alongside other exercise-induced molecules like irisin, with both contributing to cartilage homeostasis in response to physical activity. This exercise-responsive secretion pattern aligns with the defining characteristic of exerkines as molecules whose production is stimulated by physical activity.
", "therapeuticPotential": "Osteoarthritis Treatment: Recombinant lubricin supplementation has shown chondroprotective effects in animal models of osteoarthritis. In ovariectomized rats, both early and late treatment with recombinant lubricin attenuated OA progression by protecting articular cartilage from degeneration, reducing proteoglycan loss, normalizing subchondral bone remodeling, and inhibiting vascular invasion from subchondral bone to calcified cartilage. PMID 25576671
\nIn a rat anterior cruciate ligament transection model, specific lubricin mimetics improved femoral articular cartilage degeneration scores and reduced osteophyte formation without inciting additional synovial inflammation. PMID 32004084 A systematic review of lubricin supplementation studies found that all 15 papers describing intra-articular lubricin administration reported beneficial effects. PMID 32504786
\nMechanism of Chondroprotection: Lubricin prevents chondrocyte apoptosis through boundary lubrication. Studies demonstrate a direct correlation between coefficient of friction and chondrocyte death in superficial cartilage layers, with lubricin supplementation significantly lowering both friction and apoptotic cell numbers. PMID 23530215 This suggests that restoring boundary lubrication may prevent cartilage deterioration in patients with genetic or acquired lubricin deficiency. PMID 23530215
\nAnti-Inflammatory Properties: Lubricin binds to and regulates Toll-like receptors (TLRs), modulating inflammatory responses. In vitro studies show lubricin acts as an antagonist of TLR2 and TLR4, halting downstream inflammatory processes and preventing cytokine release. PMID 26752378PMID 31733682 In a rat OA model, intra-articular lubricin injections inhibited systemic inflammatory signaling and reduced pain. PMID 26752378
\nAdditional Therapeutic Applications: Lubricin has been evaluated for dry eye disease, where full-length recombinant human PRG4 (rhPRG4) demonstrated clinical efficacy in improving signs and symptoms, with in vitro studies showing reduced inflammation-induced cytokine production and MMP-9 inhibition. PMID 37678729 The protein has also been investigated as a potential therapeutic and biomarker in sepsis due to its anti-inflammatory properties. PMID 31733682
" }, "pmids": [ "23530215", "25576671", "26752378", "31733682", "32004084", "32504786", "37678729" ] }, { "id": "pf4", "shortName": "PF4", "fullName": "Platelet Factor 4 (PF4; CXCL4)", "tier": 4, "sourceTissue": "Platelets", "moleculeType": "Chemokine", "keyPathway": "CXCR3", "domains": { "cv": null, "met": null, "neuro": "primary", "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Platelet Factor 4 (PF4), also known as CXCL4, is an exercise-induced chemokine released during platelet degranulation that crosses the blood–brain barrier to promote hippocampal neurogenesis and synaptic plasticity through the activation of CXCR3 receptors PMID 41076272PMID 40818821PMID 39818278. By mitigating neuroinflammation and potentially upregulating the longevity factor Klotho, PF4 effectively reverses age-related cognitive deficits and supports brain rejuvenation, positioning it as a promising therapeutic target for Alzheimer's disease PMID 40818821PMID 39818278PMID 39335489.
", "biologicalFunction": "PF4 is classified as an exerkine because its release into the systemic circulation is robustly stimulated by physical activity, specifically through the activation of platelets.
\n1. Neuroprotection and Cognitive Rejuvenation
\n2. Sepsis, Inflammation, and Cancer
\n3. PF4 as a Target for Inhibition
\nTransforming growth factor-beta 2 (TGF-β2) is a secreted protein belonging to the transforming growth factor-beta (TGF-β) superfamily that functions as an exercise-induced signaling molecule, primarily characterized as an adipokine released from adipose tissue PMID 35304603PMID 39852400.
", "biologicalFunction": "TGF-β2 has demonstrated therapeutic potential in several clinical areas, including wound healing, bone repair, immunosuppression in transplantology, and tissue regeneration, though its role in cancer is complex and context-dependent. PMID 38964148PMID 8954178
\nTGF-β2 shows promise in wound healing and tissue repair through its ability to promote fibroblast proliferation, enhance extracellular matrix formation, and regulate angiogenesis. PMID 8954178PMID 12725873 These properties make it particularly relevant for clinical applications in wound management and tissue regeneration.
\nBone formation and repair represent another therapeutic application, as TGF-β2 plays a crucial role in regulating bone growth and is especially abundant in skeletal tissues. PMID 25709154 The TGF-β family, including TGF-β2, is considered essential in controlling metabolic homeostasis in bone tissue and the fracture healing process. PMID 25709154
\nImmunosuppressive applications have been explored, particularly in transplantology. TGF-β2 exhibits potent immunosuppressive effects by inhibiting IL-1-dependent lymphocyte proliferation and blocking lymphocyte DNA synthesis. PMID 3129508PMID 2808692 Both TGF-β1 and TGF-β2 demonstrate identical immunosuppressive effects and can suppress autoimmune T cell function. PMID 2808692
\nHowever, the therapeutic application in oncology is complicated by TGF-β2's dual role. While it can suppress tumor formation by controlling cell proliferation, tumor cells can become resistant to its growth-inhibiting properties, and TGF-β may promote tumor progression in advanced stages. PMID 38964148 This has led to strategies targeting TGF-β signaling pathway members as therapeutic targets in cancer treatment. PMID 38964148
\nThe clinical utility of TGF-β2 is supported by knockout studies showing that precise regulation of each TGF-β isoform is essential for survival, with mice deficient in TGF-β2 displaying remarkable developmental abnormalities, particularly in the cardiovascular system. PMID 38067167PMID 8954178
" }, "pmids": [ "12725873", "25709154", "2808692", "3129508", "35304603", "36633863", "38067167", "38786764", "38964148", "39335489", "39522716", "39852400", "39854050", "41213606", "8954178" ] }, { "id": "vip", "shortName": "VIP", "fullName": "Vasoactive Intestinal Peptide (VIP)", "tier": 4, "sourceTissue": "Neurons; gut; muscle vasculature", "moleculeType": "Neuropeptide", "keyPathway": "VPAC1/VPAC2; cAMP/PKA, PLC/PKC", "domains": { "cv": null, "met": null, "neuro": "primary", "msk": null, "inflam": null, "onco": null }, "sections": { "definition": "Vasoactive Intestinal Peptide (VIP) is a pleiotropic growth factor and vasodilator upregulated by acute exercise that activates VPAC receptors to potentiate hippocampal synaptic transmission and promote myelin regeneration PMID 39352588PMID 35283168. Its therapeutic potential lies in its ability to reduce neuroinflammation and reconstruct intestinal function following spinal cord injury, while also potentially supporting cognitive plasticity through the modulation of NMDA receptor currents PMID 39352588PMID 35283168.
", "biologicalFunction": "VIP is classified as an exerkine because its circulating levels are significantly modulated by physical activity, with exercise serving as a non-invasive means to enhance its expression.
\n1. Respiratory and Infectious Diseases
\n2. Neurological and Psychiatric Applications
\n3. Oncology: Agonism vs. Antagonism
\n4. Metabolic, Autoimmune, and Ocular Disorders
\n5. Pharmacology and Drug Design
\nCarbon monoxide (CO) is a \"prototypical exerkine\" produced by heme oxygenase 1 (HO-1) that functions to reduce inflammatory responses in activated macrophages PMID 39641407. By inhibiting the peripheral NLRP3 inflammasome signaling pathway alongside Irisin, exercise-induced CO contributes to the mitigation of neuroinflammation and offers potential protective effects against the progression of Alzheimer's disease PMID 39641407.
", "biologicalFunction": "CO is considered a \"prototypical exerkine\" because its production is upregulated in response to physical activity. Exercise activates the Nrf2 pathway, which in turn induces the expression of HO-1 leading to increased systemic levels of CO to mediate beneficial physiological adaptations PMID 39641407PMID 37247469.
", "therapeuticPotential": "1. Oncology and Cancer Immunotherapy
\n2. Neuroprotection and Stroke Recovery
\n3. Inflammation, Sepsis, and Organ Transplantation
\n4. Metabolic Disorders and Wound Healing
\n5. Advanced Delivery Systems
\nCathepsin B (CTSB) is an exercise-induced lysosomal cysteine protease and myokine that crosses the blood–brain barrier to promote hippocampal neurogenesis and cognitive function by upregulating neurotrophic factors like BDNF and doublecortin PMID 40818821PMID 39456173PMID 38393277. While primarily investigated for its neuroprotective ability to reduce amyloid-β plaque load in Alzheimer's disease, CTSB exhibits a complex therapeutic profile that includes inducing ferroptosis in pancreatic cancer cells and potentially mediating neuroinflammation under specific pathological conditions PMID 39988270PMID 36118704PMID 35283168.
", "biologicalFunction": "CTSB is classified as a myokine and exerkine because its secretion into the circulation is stimulated by physical activity, allowing it to mediate crosstalk between skeletal muscle and the brain.
\n1. Oncology and Enzyme-Responsive Drug Delivery
\n2. Sepsis and Inflammation
\n3. Neuroprotection and Diagnostics
\nGlycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) is an exercise-induced hepatokine that facilitates liver–brain crosstalk by cleaving GPI anchors to release membrane-bound proteins into the circulation, thereby transferring the systemic benefits of physical activity to the central nervous system PMID 40818821PMID 398182785; PMID 39456173. By upregulating brain-derived neurotrophic factor (BDNF) and suppressing the uPAR coagulation pathway, GPLD1 promotes hippocampal neurogenesis, offering therapeutic potential for mitigating age-related cognitive decline PMID 40818821PMID 39456173PMID 34782555.
", "biologicalFunction": "GPLD1 is classified as a hepatokine (liver-derived exerkine) because its circulating levels are modulated by physical activity and it mediates the systemic benefits of exercise on the brain though it is secreted by the liver.
\n1. Cardiovascular Protection
\n2. Oncology and Drug Resistance
\n