The Muscle-Brain-Adipose Tissue Axis: Mechanisms of Exercise-Induced Interorgan Cross-Communication: A Systematic Review
Keywords:
Muscle-brain-adipose tissue axis, inter-organ communication, myokines, molecular crosstalk, exercise physiologyAbstract
The classical understanding of human physiology tended to define organ systems as independent and isolated units dedicated to specific functions. However, rapid advances in the fields of systems biology, molecular endocrinology, and neuroimmunology in recent years have unequivocally revealed that the organism actually possesses a dynamic, hierarchical, and multidirectional molecular communication network. The maintenance of homeostasis is an extremely critical element for the survival of the organism and for meeting all of its needs. Skeletal muscle, which is at the center of this network, is now accepted not only as a mechanical component of the locomotor system but also as the largest and most active endocrine organ of the body. The release of hundreds of secretory proteins, termed myokines, into the systemic circulation, triggered by muscle contraction during exercise, initiates a specific communication with distant organs such as the brain, adipose tissue, liver, intestine, and bone. This molecular crosstalk, referred to as the muscle-brain-adipose tissue axis, is the fundamental mechanism explaining the profound effects of physical activity on metabolic flexibility, preservation of cognitive functions, neuroplasticity, and resistance to neurodegeneration. This review study aims to examine in depth, in light of the current literature, the exercise-regulated inter-organ communication across a wide spectrum ranging from the skeletal muscle secretome to blood-brain barrier dynamics, from microRNAs carried by extracellular vesicles to the functional transformation of adipose tissue, and its innovative perspective on human health and energy homeostasis.
References
Ahmad Ganai, S., Ramadoss, M., & Mahadevan, V. (2016). Histone deacetylase (HDAC) inhibitors-emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. Current neuropharmacology, 14(1), 55-71.
Alagiakrishnan, K., & Halverson, T. (2024). Role of peripheral and central insulin resistance in neuropsychiatric disorders. Journal of clinical medicine, 13(21), 6607.
Allan, R., Hurst, H. T., Akin, B., Liles, N., Dickson, J., Knill-Jones, J., ... & Mawhinney, C. (2026). The influence of cold temperature exposure on markers of bone health in humans: A scoping review. Journal of Thermal Biology, 104401.
Baht, G. S., Bareja, A., Lee, D. E., Rao, R. R., Huang, R., & Huebner, J. L. (2020). Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat Metab, 2, 278–289.
Berghoff, M., Höpfinger, A., Rajendran, R., Karrasch, T., Schmid, A., & Schäffler, A. (2021). Evidence of a Muscle–Brain Axis by quantification of the neurotrophic myokine METRNL (Meteorin-Like Protein) in human cerebrospinal fluid and serum. Journal of clinical medicine, 10(15), 3271.
Blume, G. R., & Royes, L. F. F. (2024). Peripheral to brain and hippocampus crosstalk induced by exercise mediates cognitive and structural hippocampal adaptations. Life sciences, 352, 122799.
Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., ... & Spiegelman, B. M. (2012). A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463-468.
Burtscher, J., Millet, G. P., Place, N., Kayser, B., & Zanou, N. (2021). The muscle-brain axis and neurodegenerative diseases: the key role of mitochondria in exercise-induced neuroprotection. International Journal of Molecular Sciences, 22(12), 6479.
Caturano, A., Galiero, R., Vetrano, E., Sardu, C., Rinaldi, L., Russo, V., ... & Sasso, F. C. (2024). Insulin–heart axis: bridging physiology to insulin resistance. International Journal of Molecular Sciences, 25(15), 8369.
Chen, J. W., Liu, M. H., Yang, Z. D., Zhu, J. S., Wang, J. X., Yang, K., ... & Ding, W. J. (2025). Erchen decoction alleviates anxiety and depression-like behaviors in high-fat diet-induced obesity mice via the Adipose–Brain axis. Journal of Ethnopharmacology, 352, 120218.
Da Costa Fernandes, C. J., da Cruz Rodrigues, K. C., de Melo, D. G., de Campos, T. D. P., dos Santos Canciglieri, R., Simabuco, F. M., ... & de Moura, L. P. (2023). Short-term strength exercise reduces the macrophage M1/M2 ratio in white adipose tissue of obese animals. Life sciences, 329, 121916.
Di Maio, G., Alessio, N., Ambrosino, A., Al Sammarraie, S. H., Monda, M., & Di Bernardo, G. (2024). Irisin influences the in vitro differentiation of human mesenchymal stromal cells, promoting a tendency toward beiging adipogenesis. Journal of Cellular Biochemistry, 125(5), e30565.
Ding, X., Wang, W., Wu, J., Li, K., Gao, H., Wu, M., ... & Xiao, W. (2025). Stimulator of interferon genes: A potential target for treating type 2 diabetes mellitus. Biochemical Pharmacology, 117491.
Duranti, E., & Villa, C. (2024). From brain to muscle: the role of muscle tissue in neurodegenerative disorders. Biology, 13(9), 719.
Fang, Y. C., Chan, L., Liou, J. P., Tu, Y. K., Lai, M. J., Chen, C. I., ... & Hu, C. J. (2020). HDAC inhibitor protects chronic cerebral hypoperfusion and oxygen‐glucose deprivation injuries via H3K14 and H4K5 acetylation‐mediated BDNF expression. Journal of Cellular and Molecular Medicine, 24(12), 6966-6977.
Fitz-James, M. H., & Cavalli, G. (2022). Molecular mechanisms of transgenerational epigenetic inheritance. Nature Reviews Genetics, 23(6), 325-341.
Hansda, S., & Das, H. (2025). Unraveling the Bone–Brain communication network. Biology, 14(9), 1279.
Hemat Jouy, S., Mohan, S., Scichilone, G., Mostafa, A., & Mahmoud, A. M. (2024). Adipokines in the crosstalk between adipose tissues and other organs: implications in cardiometabolic diseases. Biomedicines, 12(9), 2129.
Ishaq, S., Shah, I. A., Lee, S. D., & Wu, B. T. (2025). Effects of exercise training on nigrostriatal neuroprotection in Parkinson’s disease: a systematic review. Frontiers in Neuroscience, 18, 1464168.
Jeppesen, D. K., Zhang, Q., & Coffey, R. J. (2024). Extracellular vesicles and nanoparticles at a glance. Journal of Cell Science, 137(23), jcs260201.
Jessop, P., & Toledo-Rodriguez, M. (2018). Hippocampal TET1 and TET2 expression and DNA hydroxymethylation are affected by physical exercise in aged mice. Frontiers in cell and developmental biology, 6, 45.
Katayama, M., Caria, E., Van Simaeys, D., Sanz, A. Y., Barrès, R., Caidahl, K., ... & Krook, A. (2025). Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle. Journal of Sport and Health Science, 101091.
Kim, Y., Dube, S. E., & Park, C. B. (2025). Brain energy homeostasis: the evolution of the astrocyte-neuron lactate shuttle hypothesis. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 29(1), 1-8.
Kukla-Bartoszek, M., & Głombik, K. (2024). Train and reprogram your brain: effects of physical exercise at different stages of life on brain functions saved in epigenetic modifications. International Journal of Molecular Sciences, 25(22), 12043.
Latchney, S. E., Cadney, M. D., Hopkins, A., & Garland Jr, T. (2023). Maternal upbringing and selective breeding for voluntary exercise behavior modify patterns of DNA methylation and expression of genes in the mouse brain. Genes, Brain and Behavior, 22(6), e12858.
Latifkar, A., Hur, Y. H., Sanchez, J. C., Cerione, R. A., & Antonyak, M. A. (2019). New insights into extracellular vesicle biogenesis and function. Journal of cell science, 132(13), jcs222406.
Leng, S. Y., Yang, Q. H., Yuan, Y., Chen, B., Chen, H., Ban, W., & Zhang, J. (2025). Exercise modulation of gut microbiota in Alzheimer’s disease: Pathophysiological mechanisms and therapeutic perspectives. Frontiers in Aging Neuroscience, 17, 1677896.
Li, C., Li, J., Zhou, Q., Wang, C., Hu, J., & Liu, C. (2024). Effects of physical exercise on the microbiota in irritable bowel syndrome. Nutrients, 16(16), 2657.
Li, H., He, R., Luo, T., Ou, C., & Hu, Y. (2026). The jekyll and hyde of extracellular vesicles: Dual roles as disease drivers and therapeutic saviors in diabetic brain. Molecular Neurobiology, 63(1), 463.
Li, H., Liu, G., Wang, B., & Momeni, M. R. (2025). Exosomes and microRNAs as mediators of the exercise. European Journal of Medical Research, 30(1), 38.
Li, H., & Thirupathi, A. (2025). Exercise-mediated IL-6 downstream effects modulate brain pathology–can exercise training protocols influence the downstream effects?. Frontiers in neurology, 16, 1639427.
Li, Z. Y., Zheng, S. L., Wang, P., Xu, T. Y., Guan, Y. F., Zhang, Y. J., & Miao, C. Y. (2014). Subfatin is a novel adipokine and unlike Meteorin in adipose and brain expression. CNS neuroscience & therapeutics, 20(4), 344-354.
Liu, Y., Zhu, C., Guo, J., Chen, Y., & Meng, C. (2020). The neuroprotective effect of irisin in ischemic stroke. Frontiers in aging neuroscience, 12, 588958.
Maffei, M., & Giordano, A. (2022). Leptin, the brain and energy homeostasis: From an apparently simple to a highly complex neuronal system. Reviews in Endocrine and Metabolic Disorders, 23(1), 87-101.
Marjani, A. A., Nader, N. D., & Aghanejad, A. (2024). Exosomes as targeted diagnostic biomarkers: recent studies and trends. Life Sciences, 354, 122985.
Mika, A., Macaluso, F., Barone, R., Di Felice, V., & Sledzinski, T. (2019). Effect of exercise on fatty acid metabolism and adipokine secretion in adipose tissue. Frontiers in physiology, 10, 26.
Pahlavani, H. A. (2023). Exercise therapy to prevent and treat Alzheimer’s disease. Frontiers in Aging Neuroscience, 15, 1243869.
Paoletti, I., & Coccurello, R. (2024). Irisin: a multifaceted hormone bridging exercise and disease pathophysiology. International Journal of Molecular Sciences, 25(24), 13480.
Pedersen, B. K., Akerstrom, T. C., Nielsen, A. R., & Fischer, C. P. (2007). Role of myokines in exercise and metabolism. Journal of applied physiology, 103(3), 1093-1098.
Prakash, R. S., Snook, E. M., Motl, R. W., & Kramer, A. F. (2010). Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain research, 1341, 41-51.
Qin, M., Huang, Z., Wang, Y., & Ma, J. (2026). Exercise-derived exosomes mediate crosstalk between skeletal muscle, adipose tissue, and bone: mechanisms of inter-organ communication and tissue adaptation. Critical Reviews in Food Science and Nutrition, 1-18.
Raichlen, D. A., & Alexander, G. E. (2017). Adaptive capacity: an evolutionary neuroscience model linking exercise, cognition, and brain health. Trends in neurosciences, 40(7), 408-421.
Raj, J. U. (2025). Introducing the" New" comprehensive physiology: A journal focused on interorgan communication in health and disease. Comprehensive Physiology, 15(1), e9-e9.
Schöll, E. (2022). Network physiology, insights in dynamical systems: 2021. Frontiers in network physiology, 2, 961339.
Shaban, A. M., Ameen, O., Omar, M., El Derbaly, S. A., Omara, H. R., Bayomi, A. I., ... & Khodir, S. A. (2025). Treadmill training protects valproic acid-induced autistic features via cerebellar AMPK/PPAR-γ dependent pathway and improves mitochondrial activity in mice. Scientific Reports, 15(1), 25248.
Shi, H., Huang, L., Wang, Q., Zhang, N., Lv, C., Lin, C., ... & Chen, Y. (2025). The role of exercise in enhancing brain and cerebrovascular health via the bone–brain axis: implications for surgical and clinical interventions. International Journal of Surgery, 111(11), 8363-8401.
Singh, G. B., Cowan, D. B., & Wang, D. Z. (2020). Tiny regulators of massive tissue: MicroRNAs in skeletal muscle development, myopathies, and cancer cachexia. Frontiers in oncology, 10, 598964.
Sleiman, S. F., Henry, J., Al-Haddad, R., El Hayek, L., Abou Haidar, E., Stringer, T., ... & Chao, M. V. (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. elife, 5, e15092.
Son, Y., & Paton, C. M. (2020). Lipid metabolic features of skeletal muscle in pathological and physiological conditions. In Lipid signaling and metabolism (pp. 359-383). Academic Press.
Spreckley, E., & Murphy, K. G. (2015). The L-cell in nutritional sensing and the regulation of appetite. Frontiers in nutrition, 2, 23.
Sun, Z. X., Xie, F., Zhao, Y., Wang, X., Sun, Z. W., Qian, L. J., & Feng, H. (2025). Exercise and the blood–brain barrier: Mechanistic insights and therapeutic implications. Neurobiology of Disease, 107166.
Szeliga, A., Grymowicz, M., Kostrzak, A., Smolarczyk, R., Bala, G., Smolarczyk, K., ... & Suchta, K. (2024). Bone: a neglected endocrine organ?. Journal of Clinical Medicine, 13(13), 3889.
Taha, H. B., Birnbaum, A., Matthews, I., Aceituno, K., Leon, J., Thorwald, M. A., ... & Cortes, C. J. (2024). Activation of the muscle‐to‐brain‐axis reduces amyloid plaque accumulation and rescues behavioral deficits by enhancing synaptic integrity and neurotrophic signaling in a mouse model of Alzheimer’s disease. Alzheimer's & Dementia, 20, e094857.
Takeda, M., Sashide, Y., & Utugi, S. (2025). Neurophysiological basis of short-chain fatty acid action in pain modulation: Therapeutic implications. International Journal of Molecular Sciences, 26(16), 8082.
Tero-Vescan, A., Degens, H., Matsakas, A., Ștefănescu, R., Ősz, B. E., & Slevin, M. (2025). Exercise-induced muscle–fat crosstalk: molecular mediators and their pharmacological modulation for the maintenance of metabolic flexibility in aging. Pharmaceuticals, 18(8), 1222.
Van Praag, H., & Wrann, C. D. (2022). Peripheral factors and neural plasticity. Brain Plasticity, 8(1), 1-3.
Via, J., Reid, J., & Oehlert, G. (2024). Pedalling toward a deeper understanding of exercise effects on immune function. Journal of Physiology, 602(19).
Wang, L., Chen, P., & Xiao, W. (2021). β-hydroxybutyrate as an Anti-Aging metabolite. Nutrients, 13(10), 3420.
Wang, Z., & Zhu, L. (2025). New insights into lactate in exercise adaptations: does protein lactylation play a role?. American Journal of Physiology-Endocrinology and Metabolism, 329(3), E405-E419.
Williams, A., Wadsworth, D. D., & Geetha, T. (2025). Exercise, epigenetics, and body composition: Molecular connections. Cells, 14(19), 1553.
Xenos, D., Mancinetti, F., Mecocci, P., & Boccardi, V. (2025). The muscle-brain axis in type 2 diabetes: Molecular pathways linking sarcopenia and cognitive decline. Ageing Research Reviews, 102955.
Xue, X., Liu, B., Hu, J., Bian, X., & Lou, S. (2022). The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule. Nutrition & metabolism, 19(1), 52.
Yang, L., Fan, S., Sun, L., Han, J., Wang, M., & Yu, T. (2025). The role of vagus nerve stimulation in modulating Parkinson’s disease via the microbiota-gut-brain axis: a comprehensive review. Frontiers in Neurology, 16, 1643305.
Yoo, B. M., Kim, S. R., & Lee, B. W. (2025). Ketone body induction: insights into metabolic disease management. Biomedicines, 13(6), 1484.
Yu, Y., & Chen, K. (2025). Peripheral immune and metabolic regulation of Aβ and Tau by exercise in Alzheimer’s disease. Frontiers in Immunology, 16, 1678526.
Zhang, Y., Uguccioni, G., Ljubicic, V., Irrcher, I., Iqbal, S., Singh, K., ... & Hood, D. A. (2014). Multiple signaling pathways regulate contractile activity‐mediated PGC‐1α gene expression and activity in skeletal muscle cells. Physiological reports, 2(5), e12008.
Zhao, R. (2024). Exercise mimetics: a novel strategy to combat neuroinflammation and Alzheimer's disease. Journal of Neuroinflammation, 21(1), 40.
Zhou, W., Shi, Y., Wang, H., Chen, L., Yu, C., Zhang, X., ... & Wu, A. (2022). Exercise-induced FNDC5/irisin protects nucleus pulposus cells against senescence and apoptosis by activating autophagy. Experimental & molecular medicine, 54(7), 1038-1048.
Zhou, W., Zhao, L., Mao, Z., Wang, Z., Zhang, Z., & Li, M. (2023). Bidirectional communication between the brain and other organs: the role of extracellular vesicles. Cellular and Molecular Neurobiology, 43(6), 2675-2696.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Halil İbrahim YAYLA, Ramazan ERDOĞAN
This work is licensed under a Creative Commons Attribution 4.0 International License.
