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Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2026) | Viewed by 9122

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Editors

Dr. Sara Missaglia

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Laboratory of Cellular Biochemistry and Molecular Biology, Catholic University of the Sacred Heart, Milan, Italy
Interests: lipid metabolism; neutral lipid storage disease; human genetics; cellular biochemistry; molecular biology
Special Issues, Collections and Topics in MDPI journals

Dr. Eleonora Martegani

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Guest Editor

Laboratory of Cell Biochemistry and Molecular Biology, Faculty of Psychology, Catholic University of the Sacred Heart, Milan, Italy
Interests: cell biochemistry; molecular biology; neuromuscular diseases

Special Issue Information

Dear Colleagues,

Exercise induces the release of a various array of bioactive molecules, collectively known as exerkines, which play a crucial role in mediating the health benefits of physical activity. Indeed, these molecules are key regulators of muscle adaptation, metabolism, and systemic homeostasis. Moreover, they influence different physiological processes, including inflammation, mitochondrial function, tissue regeneration, and inter-organ communication, contributing to overall health and disease prevention.

In this Special Issue of Biomolecules, we aim to explore the molecular mechanisms regulating exerkine release and function, the impact on skeletal muscle physiology, and their broader effects on metabolic and cardiovascular health, ageing, neurocognitive improvement, and neuroprotection. We welcome original research and review articles covering exercise-modulated exerkine signalling, exerkine-mediated crosstalk between muscle and other organs, their role in metabolic disorders, and novel therapeutic applications of exercise-induced factors.

Dr. Sara Missaglia
Dr. Eleonora Martegani
Guest Editors

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Keywords

exerkines
myokines
adipokines
cytokines
exercise-induced benefits

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Published Papers (8 papers)

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Research

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23 pages, 1231 KB

Open AccessArticle

Non-Work-Matched HIIT and MIIT Partially Restore Exerkine-Related and Mitochondrial Gene Expression in Diabetic Rat Skeletal Muscle

by Saeed Rezae, Payam Abasian Mehr, Parisa Pournemati, Ismail Laher, Özgür Eken and Monira I. Aldhahi

Biomolecules 2026, 16(8), 1152; https://doi.org/10.3390/biom16081152 - 7 Aug 2026

Abstract

Skeletal muscle mitochondrial dysfunction and altered myokine signaling contribute to insulin resistance in type 2 diabetes. This study compared the effects of non-work-matched high-intensity interval training (HIIT) and moderate-intensity interval training (MIIT) on skeletal muscle exerkine/myokine- and mitochondrial biogenesis-related gene expression and systemic metabolic indices in streptozotocin-nicotinamide-induced diabetic rats. Twenty-four male Wistar rats were initially allocated to healthy control, diabetic control, MIIT, or HIIT groups; after predefined treadmill-familiarization exclusions, five animals per group were analyzed. Training was performed for 6 weeks, three sessions per week, with MIIT prescribed at 70% maximal aerobic speed and HIIT at 90% maximal aerobic speed. Gastrocnemius expression of FNDC5, OSTN, PGC-1α, TFAM, CCO, and UCP3 was quantified by RT-qPCR, and fasting glucose, insulin, lipid variables, HOMA-IR, HOMA-β, QUICKI, and TyG index were assessed. Diabetes reduced all targeted transcripts and impaired insulin-related metabolic indices. Both MIIT and HIIT partially restored myokine- and mitochondrial-related transcripts compared with diabetic controls, with no significant differences between training protocols for most molecular outcomes. HIIT produced lower fasting insulin and HOMA-IR than MIIT but imposed a greater estimated cumulative workload. These findings indicate that interval training partly attenuates diabetes-associated transcriptional and insulin-related metabolic disturbances, while intensity-specific conclusions require work-matched designs. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

14 pages, 1632 KB

Open AccessArticle

Acute Resistance Exercise Temporarily Reduces Circulating Adiponectin in Trained Young Men: A Pilot Study

by Luigi Marano, Marta Mallardo, Ersilia Nigro, Furqan Memon, Viktoriia Fylymonenko, Eleonora Martegani, Sara Missaglia, Ferdinando Cereda, Daniela Tavian and Aurora Daniele

Biomolecules 2026, 16(2), 229; https://doi.org/10.3390/biom16020229 - 2 Feb 2026

Viewed by 686

Abstract

Background: Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, and cytoprotective properties that also plays a key role in metabolic adaptation to exercise. Although its regulation after resistance exercise has been extensively documented, less is known about its short-term modulation and its correlation with muscle damage markers following resistance training. Methods: Nine resistance-trained young men completed two sessions of total-body resistance exercise: (1) high time under tension (TUT) (5-1-2-1 cadence, to failure; ETS1) and (2) moderate TUT (2-1-2-1 cadence, two repetitions in reserve; ETS2). Plasma and saliva samples were collected before exercise and at 15 min, 24 h, and 48 h after exercise to assess total adiponectin by ELISA. Plasma creatine kinase (CK) and a Visual Analog Scale (VAS) were also measured for muscle soreness. Results: Plasma adiponectin significantly decreased from baseline to 48 h post-exercise in both sessions (p < 0.001), with no differences between the TUT conditions. Salivary adiponectin remained unchanged. Although a significant increase in CK and a decrease in adiponectin were observed at the group level, correlation analysis revealed no significant linear relationship between the magnitude of CK elevation and adiponectin reduction. Conclusions: Overall, these findings support the role of adiponectin as a marker of acute metabolic adaptation to resistance exercise. Acute resistance exercise elicited a time-dependent decrease in circulating adiponectin, irrespective of TUT. The temporal pattern of adiponectin decrease coincided with the rise in muscle damage markers, yet the lack of direct correlation suggests distinct regulatory mechanisms, while the lack of salivary changes underscores the complexity of adipokine regulation in vivo and suggests that saliva is not a reliable indicator of changes in circulating adiponectin. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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Review

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25 pages, 2282 KB

Open AccessReview

Lactate as a Cardiovascular Exerkine: Mechanisms, Signaling Pathways, and Clinical Implications

by Francesco Vari, Ilaria Serra, Elisa Bisconti, Daniele Vergara and Anna M. Giudetti

Biomolecules 2026, 16(7), 943; https://doi.org/10.3390/biom16070943 - 24 Jun 2026

Viewed by 596

Abstract

Lactate was traditionally considered a metabolic by-product of anaerobic glycolysis, mainly associated with tissue hypoxia and muscle fatigue. However, increasing evidence has redefined lactate as a multifunctional metabolic intermediate and signaling molecule involved in exercise-induced systemic adaptations. During physical activity, circulating lactate levels rise markedly when skeletal muscle production exceeds systemic clearance, allowing lactate to act as an exercise-responsive metabolite, or exerkine, and as a mediator of cardiometabolic adaptation. In the cardiovascular system, lactate serves not only as an efficient substrate for myocardial energy production but also as a regulator of vascular tone, endothelial function, angiogenesis, inflammation, and cardiac remodeling. These effects occur through receptor-dependent and receptor-independent mechanisms, including activation of hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), modulation of intracellular redox balance, and histone or non-histone protein lactylation. This review summarizes current evidence on lactate in cardiovascular physiology and disease, focusing on myocardial lactate metabolism, HCAR1/GPR81 signaling, protein lactylation, extracellular vesicle communication, gut microbiota interactions, and therapeutic implications in heart failure, atherosclerosis, and diabetic cardiomyopathy. Although lactate is also produced under resting, postprandial, and pathological conditions, exercise is characterized by the amplitude and kinetics of lactatemia, coordinated hormonal and hemodynamic responses, and transient high-concentration signaling. These features support exercise-derived lactate as a context-dependent cardiovascular exerkine. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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34 pages, 667 KB

Open AccessReview

Exercise Intensity and Circulating Exerkine Responses: A Narrative Review of Selected Molecules

by Yanqi Zhao, Tutu Wang, Xinuan Zhang, Wange Wang, Yu Fu, Ismail Laher and Shunchang Li

Biomolecules 2026, 16(6), 852; https://doi.org/10.3390/biom16060852 - 10 Jun 2026

Viewed by 629

Abstract

Exerkines are bioactive molecules released in response to physical exercise and are considered important mediators of systemic adaptations. While previous research has largely focused on the effects of exercise modalities, the role of exercise intensity in regulating exerkine responses remains unclear. This narrative review summarizes findings on the effects of different exercise intensities on nine circulating exerkines with sufficient available data in healthy populations, including irisin, follistatin-like 1, myostatin, fibroblast growth factor 21, follistatin, leptin, adiponectin, apelin and brain-derived neurotrophic factor, without systematically covering all known exercise-responsive molecules. Given the narrative design of this review, the findings should be interpreted as descriptive and hypothesis-generating rather than as definitive evidence of intensity-dependent effects. The included studies show that acute exercise is associated with changes in several exerkines, with some direct within-study comparisons reporting larger responses under higher-intensity exercise conditions, whereas others exhibit increases, decreases, or no measurable changes across intensities. In contrast, studies examining chronic exercise interventions report changes in some studies and no measurable differences in others. Overall, the current evidence in this review suggests that exercise intensity may influence exerkine responses under some conditions, particularly during acute exercise, although the available findings remain limited and inconsistent across studies. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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19 pages, 663 KB

Open AccessReview

Potential Influence of Myokines on Skeletal Muscle Tissue Hypertrophy Signaling Pathways: A Narrative Review

by Stephen M. Cornish and Jose Peralta-Huertas

Biomolecules 2026, 16(6), 850; https://doi.org/10.3390/biom16060850 - 10 Jun 2026

Viewed by 611

Abstract

Sarcopenia is defined as the age-related loss of skeletal muscle strength, power, and size. Understanding the fundamental mechanisms whereby sarcopenia occurs is an area of research that has received much attention due to the aging population. Skeletal muscle tissue is used for locomotion and acts as a major site aiding the regulation of metabolism. Myokines are cytokines released from skeletal muscle tissue that act in an autocrine, paracrine, or endocrine manner. Myokines have been termed the ‘exercise factor’ or ‘work factor’ that scientists have long thought communicate between skeletal muscle and various physiological systems, including muscle-to-muscle cross-talk. One area of research that has been underexplored is the effect that myokines may have in an autocrine manner on skeletal muscle tissue itself. Although the myokine role in skeletal muscle hypertrophy and atrophy has been somewhat elucidated in rodent models, relatively little research has been performed in human models to understand the role myokines have on anabolic and catabolic metabolism in an autocrine manner. This review will provide an overview of myokine function within a biological context, some molecular pathways involved in skeletal muscle anabolism, a mechanistic understanding of myokine autocrine action, key evidence in relation to skeletal muscle satellite cell interaction with myokines, how myokines may be involved in skeletal muscle regeneration, and an outline of some key myokines that have the potential to act in an anabolic fashion within skeletal muscle. The review will then emphasize some important areas of research that are needed to understand the role of myokines in maintaining or improving skeletal muscle mass within an aging context. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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12 pages, 557 KB

Open AccessReview

Irisin as an Exerkine of Neuroprotection in Aging and Alzheimer’s Disease

by Zachary J. White and Stephanie E. Hall

Biomolecules 2026, 16(5), 687; https://doi.org/10.3390/biom16050687 - 6 May 2026

Viewed by 1004

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease impacting over 6 million Americans, with cases projected to increase to over 14 million by 2060. The AD pathology leads to difficulty completing everyday tasks or conversations, and ultimately, progresses to disrupt the most basic bodily functions and require full-time caretaking. While disease-modifying therapy remains elusive, reducing the incidence of AD is crucial to mitigate the projected increase in cases. Exercise has emerged as an effective strategy to promote brain health in late adulthood and to protect against the onset of AD. Exercise opposes several disease processes, including cognitive dysfunction, amyloid beta aggregation, tau phosphorylation, and deficits in hippocampal volume, mitochondrial function, cerebral blood flow, and neurogenesis, through various pathways, including the systemic release of exerkines. The exerkine irisin is an important mediator of the beneficial relationship between exercise and the brain. Previous work administering irisin therapeutically to healthy and preclinical AD mice has demonstrated irisin use to replicate multiple exercise-induced effects in the brain and protect against AD-induced deficits. Although irisin is suggested as a promising strategy for promoting brain health in late adulthood, our understanding of irisin signaling and its protective effects against AD remains incomplete. This review will investigate irisin as an important, physiologically relevant promoter of brain health in aging and AD. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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25 pages, 937 KB

Open AccessReview

From Fat to Brain: Adiponectin as a Mediator of Neuroplasticity in Depression

by Patrizia Genini, Ilari D’Aprile, Giulia Petrillo, Maria Grazia Di Benedetto, Veronica Begni, Nadia Cattane and Annamaria Cattaneo

Biomolecules 2025, 15(12), 1642; https://doi.org/10.3390/biom15121642 - 22 Nov 2025

Cited by 4 | Viewed by 2185

Abstract

Depression is a leading cause of global disability and is increasingly recognized as a multifactorial disorder characterized by fundamental disruptions in neuroplasticity, including diminished hippocampal neurogenesis, impaired synaptic plasticity, and dysregulated stress-response systems. Given the limited efficacy of conventional pharmacological treatments, lifestyle-based interventions—most notably physical exercise—have gained considerable attention for their antidepressant effects, partly mediated by secreted exerkines. Among these, adiponectin has emerged as a particularly compelling candidate linking metabolic regulation to neuroplasticity and mood. Recent evidence suggests that adiponectin contributes to the antidepressant effects of exercise by modulating hippocampal neurogenesis, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. Despite these advances, the mechanisms by which adiponectin influences depression remain incompletely understood. This review synthesizes current knowledge on adiponectin’s role in depression pathophysiology, with emphasis on its capacity to enhance neuroplasticity and hippocampal neurogenesis, and its potential to mediate exercise-induced antidepressant effects via defined molecular pathways. Building on these insights, we discuss adiponectin’s translational promise as both a predictive biomarker of treatment response and a novel therapeutic target. By integrating preclinical and clinical evidence, this review offers a comprehensive perspective on adiponectin’s involvement in depression while identifying critical gaps to guide future mechanistic research. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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15 pages, 1971 KB

Open AccessSystematic Review

Short-Lived Exercise-Induced Exerkines Modulate Inflammation for Chronic Disease Prevention: A Systematic Review and Meta-Analysis

by Hossein Poorhabibi, Katja Weiss, Thomas Rosemann, Beat Knechtle, Rasoul Eslami, Bakhtyar Tartibian, Seyed Morteza Tayebi and Rahman Sheikhhoseini

Biomolecules 2025, 15(11), 1590; https://doi.org/10.3390/biom15111590 - 13 Nov 2025

Cited by 5 | Viewed by 2194

Abstract

Physical exercise triggers the release of short-lived exerkines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10), which may help reduce systemic inflammation and mitigate the risk of chronic disease. Despite their potential, the effects of these exercise-induced cytokines (termed exerkines) across diverse populations remain underexplored. This study evaluated how exercise-induced exerkines modulate inflammatory markers, based on changes observed before and after intervention. We systematically searched PubMed, Scopus, and Web of Science from January 2015 up to 7 February 2025, identifying 11 randomized controlled trials (RCTs) involving 1135 participants. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model to assess changes in IL-6, TNF-α, IL-10, C-reactive protein (CRP), and interferon-gamma (IFN-γ). Study quality was evaluated using the Cochrane Risk of Bias 2 tool. Exercise significantly reduced CRP (SMD = −0.77, 95% CI: −1.20 to −0.33, p = 0.001) and TNF-α (SMD = −1.09, 95% CI: −2.14 to −0.03, p = 0.043) while increasing IL-6 (SMD = 0.81, 95% CI: 0.10 to 1.53, p = 0.026). IL-10 showed a non-significant increase (SMD = 0.66, 95% CI: −0.09 to 1.41, p = 0.084), with no effect on IFN-γ. Heterogeneity was moderate for CRP (I² = 52.5%) but high for other markers (I² > 87%). These findings suggest that exerkines contribute to an anti-inflammatory shift in the short term, which is consistent with mechanisms that may underlie the preventive effects of exercise against cardiometabolic diseases; however, standardized protocols and longitudinal studies with clinical endpoints are needed to confirm any long-term benefits. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

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