Myokines as mediators of muscle–brain crosstalk: Implications for neuroplasticity and neurodegenerative diseases

Vollständiger Abstract

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Background: Skeletal muscle is increasingly recognized as an endocrine organ that releases bioactive factors, termed myokines, capable of mediating inter-organ communication, including signaling to the brain. Aim: To summarize current evidence on key myokines involved in muscle–brain crosstalk and their potential roles in neuroplasticity, cognition, and neurodegenerative diseases. Methods: This narrative review synthesizes findings from experimental and clinical studies addressing exercise-induced myokines, their interaction with the blood–brain barrier, and associated intracellular signaling pathways relevant to central nervous system function. Results: Multiple myokines, including fibronectin type III domain-containing protein 5 (irisin), cathepsin B, insulin-like growth factor-1, interleukin-6, interleukin-1, leukemia inhibitory factor, and lactate, have been implicated in muscle–brain communication. These factors may influence brain function by crossing or modulating the blood–brain barrier and activating signaling pathways such as protein kinase B, extracellular signal-regulated kinases, and cAMP response element-binding protein. Evidence suggests that these mechanisms contribute to increased brain-derived neurotrophic factor expression, promoting neurogenesis, synaptic plasticity, and neuroprotection. Additionally, creatine, although not a myokine, may support brain function through its role in cellular energy homeostasis. Conclusion: Myokines represent key mediators linking physical exercise to brain health, with potential implications for the prevention and management of neurodegenerative conditions. However, further studies are required to clarify their mechanisms and clinical applicability. Relevance for Patients: Understanding how exercise-induced factors influence brain function may support the development of non-pharmacological and adjunct therapeutic strategies to preserve cognitive function and reduce the risk of neurodegenerative diseases.