Skeletal muscle as an endocrine organ: The myokinome, interorgan crosstalk, and pathophysiological implications a comprehensive review

Background: Skeletal muscle is now firmly established as the largest secretory organ in the human body. Far from serving merely locomotor and metabolic fuel-consuming roles, contracting muscle elaborates a diverse repertoire of bioactive peptides, proteins, and metabolites—collectively termed myokines or, more broadly, exerkines—that regulate the function of virtually every major organ system. Understanding this secretome has transformed our conception of physical activity from a mechanical intervention to a bona fide endocrine stimulus.This review synthesizes current biochemical, molecular, and translational evidence regarding the identity, regulation, and systemic actions of skeletal muscle-derived secretory factors. We examine the intracellular signaling cascades—including AMPK, PGC-1α isoforms, CaMKII, and JAK/STAT3 pathways—that govern myokine transcription and release, and detail interorgan crosstalk axes spanning the muscle–liver, muscle–adipose, muscle–bone, muscle–brain, and muscle–immune interfaces. We further discuss how myokine dysregulation contributes to the pathogenesis of type 2 diabetes, non-alcoholic steatohepatitis, sarcopenia, Alzheimer's disease, and malignancy, and evaluate the emerging therapeutic landscape of myokine mimetics and exercise pharmacology.Themyokinome constitutes a biochemically coherent endocrine network that mechanistically links physical activity to systemic health outcomes. Decoding this network offers a rational foundation for exercise prescription as targeted endocrine therapy and for the development of myokine-based pharmacologics in cardiometabolic, neurodegenerative, and oncological disease.