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Molecular and Physiological Mechanisms of Exercise

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 38427

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Dr. Zoran Nikolovski

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Guest Editor

Faculty of Kinesiology, University of Split, 21000 Split, Croatia
Interests: biochemistry; pharmacology; genetics; molecular biology; sports medicine; exercise physiology; antidoping

Special Issue Information

Dear Colleagues,

Molecular biology has its place at the point of connection between biochemistry and genetics, seeking to determine the molecular mechanisms underlying vital cellular functions. More specifically, the study of molecular mechanisms, as directed toward the underlying mechanisms behind athletic performance, has seen advances made in the development and refinement of omics technologies. Multi-Omics, a combination of the fields of genomics, proteomics, transcriptomics, metabolomics, metagenomics, and epigenomics—together with recently improved analyses of big data, artificial intelligence, and bioinformatics—is opening the door to extraordinary possibilities for better understanding the cellular functions and molecular mechanisms of exercise in professional and amateur athletes of all ages.

This combination of omics data may aid efforts in identifying biochemical biomarkers and/or genes related to athletic performance, fatigue, nutrition, energetics, overtraining, stress, inflammation, cardiorespiratory function, sensitivity to injuries, and more. Subsequently, this can bring about predictions of gene expression and molecular characteristics of athletic performance, broaden the understanding of the mechanisms of biochemistry and the physiology of exercise, and potentially open avenues for understanding connections between numerous gene expressions and their effects on molecules involved in nutrition, metabolism and energetics, immune response, inflammation, stress, and hormonal control related to sport and exercise.

As a result, the emerging field of metagenomics raises the possibility of studying relationships that are not limited to already established connections between the gut and brain or the gut and muscles, moving beyond these fields instead.

We therefore invite authors to submit original research papers and review articles with a focus on application for practitioners in the field of athletic performance and health improvement. In particular, we encourage both scientists and practitioners to provide their contributions to this Special Issue.

Topics of interest for this Special Issue include, but are not limited to, the connections between gene expression and their effect on molecules involved in the following areas:

Nutrition;
Metabolism and energetics;
Immune response;
Inflammation;
Stress;
Hormonal control related to sport and exercise;
Prevention and injury reduction in sports.

Dr. Zoran Nikolovski
Guest Editor

Manuscript Submission Information

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Keywords

molecular biology
biochemistry and exercise
athletic performance
multi-omic

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Published Papers (8 papers)

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Review

48 pages, 3549 KB

Open AccessReview

Exercise-Induced Hepatic Mitochondrial Reprogramming Across Muscle–Gut–Thyroid Axes in MASLD/MASH

by Jonas M. McCaffrey and Jamal A. Ibdah

Int. J. Mol. Sci. 2026, 27(14), 6112; https://doi.org/10.3390/ijms27146112 - 8 Jul 2026

Viewed by 634

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health burden driven by complex interactions among hepatic lipid accumulation, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Exercise remains the cornerstone of lifestyle therapy for MASLD/MASH; however, its therapeutic benefits extend well beyond weight reduction and involve coordinated molecular adaptations across multiple organ systems. In this review, we introduce hepatic mitochondrial reprogramming as a conceptual framework describing the coordinated remodeling of mitochondrial energetics, quality-control pathways, and redox homeostasis that collectively restore metabolic flexibility and hepatocellular resilience. Exercise activates key metabolic regulators, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuin signaling, promoting mitochondrial biogenesis, fatty acid oxidation, oxidative phosphorylation, and mitophagy while suppressing hepatic lipogenesis and oxidative injury. Skeletal muscle-derived myokines, alterations in gut microbial metabolism, and thyroid hormone signaling converge upon hepatic mitochondrial function through complementary endocrine and metabolic pathways. Together, these adaptations reduce hepatic steatosis, lipotoxicity, inflammation, and fibrogenesis while improving insulin sensitivity and metabolic flexibility. Emerging evidence further suggests that exercise-induced mitochondrial remodeling may complement pharmacologic therapies targeting hepatic metabolism, including thyroid hormone receptor-β agonists. Although multi-omics technologies continue to expand our understanding of these adaptive responses, the present review emphasizes the underlying molecular and physiological mechanisms through which exercise remodels hepatic mitochondrial function. We propose that exercise acts as a systems-level mitochondrial remodeling stimulus integrating skeletal muscle-, gut-, and thyroid-derived signals to improve hepatic metabolism and attenuate MASLD/MASH progression. This conceptual framework provides a mechanistic basis for precision exercise prescriptions and future combination therapeutic strategies targeting mitochondrial health. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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29 pages, 5821 KB

Open AccessReview

Myokine Signaling in Sarcopenia-Associated Chronic Musculoskeletal Pain: A Systematic Review of Inflammatory Mechanisms

by Hae Sung Lee, Ijoon Kim, Jong-Geun Kim and Yae-Young Kim

Int. J. Mol. Sci. 2026, 27(12), 5204; https://doi.org/10.3390/ijms27125204 - 9 Jun 2026

Cited by 1 | Viewed by 755

Abstract

Chronic musculoskeletal pain and sarcopenia co-occur at rates exceeding epidemiological independence in older adults. However, no systematic review has examined whether exercise-induced myokine signaling suppresses shared NF-κB–driven inflammatory pathways to concurrently address chronic pain and sarcopenic muscle loss in older adults. Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, Scopus, and Embase (January 2000–March 2026) and included 32 studies (RCTs, cohort, cross-sectional, and mechanistic designs) in adults aged ≥45 years with chronic musculoskeletal pain and/or sarcopenia; studies lacking an exercise component or human mechanistic relevance were excluded, and findings were qualitatively synthesized. The included studies suggest that persistent NF-κB hyperactivation—driven by SASP, LPS–TLR4 signaling, and mitochondrial ROS—is associated with both sarcopenic muscle loss and pain sensitization. Evidence from included studies indicates that contracting skeletal muscle secretes IL-6, IL-15, irisin, BDNF, and myostatin, which were frequently associated with suppression of NF-κB activity, attenuation of NLRP3 inflammasome activation, and improvement in pain inhibition—suggesting a hypothesized shared mechanistic pathway that awaits direct validation in trials enrolling older adults with co-confirmed sarcopenia and chronic pain. Multicomponent training emerged as the modality most consistently associated with concurrent benefits for both conditions across included studies. The synthesized evidence supports considering a two-phase approach—pain neuroscience education followed by progressive resistance training—as a hypothesis-driven framework to improve exercise adherence and myokine responses. These findings suggest that myokine signaling represents a plausible shared mechanistic pathway linking exercise to concurrent improvements in sarcopenia and chronic pain, warranting direct validation in future trials. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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24 pages, 1412 KB

Open AccessReview

Biomarkers as Temporal Signals: A Decision-Linked Multi-Layer Framework for Exercise Recovery, Overload, and Adaptation

by Dan Cristian Mănescu, Camelia Daniela Plăstoi, Ancuța Pîrvan, Cristina Daniela Pașcan, Lucian Păun, Ionuț Eduard Sersea, Bogdan Niculescu, Viorela Elena Popescu, Andreea Voinea and Andreea Popescu

Int. J. Mol. Sci. 2026, 27(8), 3675; https://doi.org/10.3390/ijms27083675 - 20 Apr 2026

Cited by 2 | Viewed by 752

Abstract

Exercise adaptation and training maladaptation arise from overlapping metabolic, redox, inflammatory, endocrine, and tissue-remodeling processes, so the translational question is not whether biomarkers change but when, where, and for which decision they become informative. This narrative review develops a decision-linked framework for minimally invasive biomarkers across the recovery–overload continuum and treats biomarker meaning as a molecule–matrix–time–decision relationship rather than as a stand-alone peak. The framework is organized around five coupled layers: stimulus architecture, signaling and release biology, sampling matrix and pre-analytics, bout-relative kinetics, and the monitoring decision to be supported. Current evidence indicates that no single biomarker reliably separates productive remodeling from delayed recovery, tissue strain, non-functional overreaching, or early maladaptation. Classical chemistry remains useful for bounded tasks, especially delayed tissue strain and stress reactivity; cfDNA appears promising for rapid load sensitivity; targeted metabolite panels are strongest for recovery phenotyping; and circulating RNAs and extracellular-vesicle cargo add mechanistic depth but remain constrained by pre-analytical fragility and incomplete standardization. The central practical implication is that overload is better interpreted as progressive loss of signal resolution than as threshold-crossing and that sparse temporally staggered panels are more likely to aid monitoring decisions than isolated markers or untimed high-dimensional profiles. Progress will depend on purpose-specific panels, transparent analytical standards, and prospective validation against symptoms, performance, and established measures across sex, hormonal, circadian, and training contexts. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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23 pages, 2869 KB

Open AccessReview

Canonical and Alternative Pathways (Insulin and Exercise) of GLUT4 Synthesis, Signaling, Intracellular Clustering, and Recruitment to the Plasma Membrane

by Arnulfo Ramos-Jiménez, Mariazel Rubio-Valles, Jaime Guereca-Arvizuo, Marco A. Juárez-Oropeza, Javier A. Ramos-Hernández, Isaac A. Chávez-Guevara, Everardo González-Rodríguez, Verónica Moreno-Brito and Rosa P. Hernández Torres

Int. J. Mol. Sci. 2026, 27(8), 3475; https://doi.org/10.3390/ijms27083475 - 13 Apr 2026

Cited by 2 | Viewed by 2855

Abstract

Glucose transporter type 4 (GLUT4), encoded by the SLC2A4 gene, is the final effector of insulin-stimulated glucose uptake in insulin-sensitive tissues: skeletal muscle, adipose tissue, and cardiac muscle. Its dynamic localization, retained intracellularly under basal conditions and extensively translocated to the plasma membrane upon stimulation, makes it a master regulator of glycemic homeostasis. While the canonical insulin pathway (PI3K/Akt/TBC1D4) is the most potent and specific mechanism in the postprandial state, its dysfunction is centrally associated with insulin resistance and type 2 diabetes mellitus (T2DM). Crucially, robust alternative signaling networks function completely independently of insulin to regulate GLUT4 synthesis and translocation. Prominent among these are contraction-mediated pathways in skeletal muscle, which employ calcium signaling (via CaMKII), mechanical/metabolic stress sensors (via p38 MAPK γ/δ), and AMP-activated protein kinase (AMPK). This review critically integrates current knowledge, linking the molecular architecture and post-translational modifications of GLUT4 to the complex, tissue-specific signaling networks that govern its vesicular trafficking. We emphasize the hierarchy, redundancy, and interdependence of these pathways, highlighting differences between acute translocation and chronic transcriptional adaptations. Finally, we discuss how deciphering insulin-independent mechanisms offers promising therapeutic opportunities, particularly in identifying pharmacological targets that mimic the metabolic benefits of physical exercise. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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41 pages, 1522 KB

Open AccessReview

Socceromics: A Systematic Review of Omics Technologies to Optimize Performance and Health in Soccer

by Adam Owen, Halil İbrahim Ceylan, Piotr Zmijewski, Carlo Biz, Giovanni Sciarretta, Alessandro Rossin, Pietro Ruggieri, Andrea De Giorgio, Carlo Trompetto, Nicola Luigi Bragazzi and Luca Puce

Int. J. Mol. Sci. 2026, 27(2), 749; https://doi.org/10.3390/ijms27020749 - 12 Jan 2026

Cited by 2 | Viewed by 2762

Abstract

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., ACE, AGT, NOS3, VEGF, ADRA2A, ADRB1–3) were associated with endurance, cardiovascular regulation, and recovery. Genes related to muscle structure, metabolism, and hypertrophy (e.g., ACTN3, CKM, MLCK, TRIM63, TTN-AS1, HIF1A, MSTN, MCT1, AMPD1) were linked to sprint performance, metabolic efficiency, and muscle injury susceptibility. Neurotransmission-related genes (BDNF, COMT, DRD1–3, DBH, SLC6A4, HTR2A, APOE) influenced motivation, fatigue, cognitive performance, and brain injury recovery. Connective tissue and extracellular matrix genes (COL1A1, COL1A2, COL2A1, COL5A1, COL12A1, COL22A1, ELN, EMILIN1, TNC, MMP3, GEFT, LIF, HGF) were implicated in ligament, tendon, and muscle injury risk. Energy metabolism and mitochondrial function genes (PPARA, PPARG, PPARD, PPARGC1A, UCP1–3, FTO, TFAM) shaped endurance capacity, substrate utilization, and body composition. Oxidative stress and detoxification pathways (GSTM1, GSTP1, GSTT1, NRF2) influenced recovery and resilience, while bone-related variants (VDR, P2RX7, RANK/RANKL/OPG) were associated with bone density and remodeling. Beyond genomics, proteomics identified markers of muscle damage and repair, metabolomics characterized fatigue- and energy-related signatures, and microbiomics revealed links between gut microbial diversity, recovery, and physiological resilience. Evidence from omics research in soccer supports the potential for individualized approaches to training, nutrition, recovery, and injury prevention. By integrating genomics, proteomics, metabolomics, and microbiomics data, clubs and sports practitioners may design precision strategies tailored to each player’s biological profile. Future research should expand on multi-omics integration, explore gene–environment interactions, and improve representation across sexes, age groups, and competitive levels to advance precision sports medicine in soccer. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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25 pages, 4214 KB

Open AccessReview

Extracellular Vesicles in Sport Horses: Potential Biomarkers and Modulators of Exercise Adaptation and Therapeutics

by Dominika Milczek-Haduch, Magdalena Żmigrodzka and Olga Witkowska-Piłaszewicz

Int. J. Mol. Sci. 2025, 26(9), 4359; https://doi.org/10.3390/ijms26094359 - 3 May 2025

Cited by 9 | Viewed by 2357

Abstract

Significant systemic metabolic benefits result from even a single exercise session by activating multiple metabolic and signaling pathways within the organism. Among these mechanisms, extracellular vesicles (EVs) play a critical role by delivering their molecular cargo to neighboring or distant cells, thereby influencing cellular metabolism and function. As research progresses, EVs represent an exciting frontier in exercise science and fitness adaptation processes. There is increasing interest in understanding the physiology of EVs as signaling particles and their use as minimally invasive diagnostic and prognostic biomarkers in the early detection of oxidative stress-related abnormalities. They also show potential to be used in monitoring exercise progress, injury prevention, or recovery, and may provide insights for personalized training programs. This review examines the current understanding of the role of physical activity in generating exercise-responsive EVs. It highlights the potential applications of EVs in exercise science and personalized fitness optimization, not only for human athletes but also for exercising animals such as horses. On the other hand, it also presents potential difficulties that researchers currently working on this topic may encounter due to technical limitations. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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23 pages, 3305 KB

Open AccessReview

CSE/H₂S Signaling Pathways in Enhancing Muscle Function and Insulin Sensitivity During Exercise

by Miaomiao Xu, Xiaoguang Liu, Danting Hu, Zhaowei Li and Liming Lu

Int. J. Mol. Sci. 2025, 26(4), 1741; https://doi.org/10.3390/ijms26041741 - 18 Feb 2025

Cited by 7 | Viewed by 3574

Abstract

Exercise plays a crucial role in maintaining metabolic health, enhancing muscle function, and improving insulin sensitivity, thereby preventing metabolic diseases such as type 2 diabetes. Emerging evidence highlights the significance of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H₂S) signaling pathway as a pivotal regulator in the molecular and physiological adaptations induced by exercise. This review comprehensively examines the biosynthesis and metabolism of H₂S, its distribution in different muscle tissues, and the mechanisms by which CSE/H₂S influences muscle contraction, repair, and protein synthesis. Additionally, it explores how CSE/H₂S modulates insulin signaling pathways, glucose uptake, and lipid metabolism, thereby enhancing insulin sensitivity. The potential of H₂S donors as exercise supplements is also discussed, highlighting their ability to improve exercise performance and metabolic health. Current research advancements, including the application of multi-omics approaches, are reviewed to provide a deeper understanding of the complex molecular networks involved. Furthermore, the challenges and future directions in CSE/H₂S research are addressed, emphasizing the need for further mechanistic studies and clinical applications. This review underscores the therapeutic potential of targeting the CSE/H₂S pathway to optimize the benefits of exercise and improve metabolic health. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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18 pages, 332 KB

Open AccessReview

Nutritional Strategies for Enhancing Performance and Training Adaptation in Weightlifters

by Dong-Joo Hwang and Hong-Jun Yang

Int. J. Mol. Sci. 2025, 26(1), 240; https://doi.org/10.3390/ijms26010240 - 30 Dec 2024

Cited by 9 | Viewed by 23203

Abstract

Weightlifting demands explosive power and neuromuscular coordination in brief, repeated intervals. These physiological demands underscore the critical role of nutrition, not only in optimizing performance during competitions but also in supporting athletes’ rigorous training adaptations and ensuring effective recovery between sessions. As weightlifters strive to enhance their performance, well-structured nutritional strategies are indispensable. In this comprehensive review, we explored how weightlifters can optimize their performance through targeted nutritional strategies, including carbohydrate intake for glycogen replenishment and proteins for muscle growth and recovery. Additionally, the roles of key supplements, such as creatine, beta-alanine, and branch-chained amino acids in enhancing strength, delaying fatigue, and supporting muscle repair were discussed. A comprehensive literature review was conducted using PubMed, Google Scholar, and Web of Science to gather studies on nutritional strategies for weightlifting performance and training adaptation. The review focused on English-language articles relevant to weightlifters, including studies on powerlifting, while excluding those involving non-human subjects. Weightlifting requires explosive power, and proper nutrition is vital for performance and recovery, emphasizing the role of carbohydrate, protein, and fat intake. Nutrient timing and personalized strategies, informed by genetic and metabolomic analyses, enhance recovery and performance, while supplements like creatine, caffeine, and beta-alanine can significantly improve results when used correctly. Sustainable nutritional strategies are essential for enhancing weightlifter performance, emphasizing a balanced approach over extreme diets or excessive supplements. Further research is needed to refine these strategies based on individual athlete characteristics, ensuring consistent top-level performance throughout competitive seasons. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

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