Background: Skeletal muscle, once regarded solely as a contractile tissue, is now recognized as a dynamic endocrine organ secreting exercise-induced myokines—bioactive peptides with autocrine, paracrine, and endocrine functions. These myokines coordinate systemic energy homeostasis by regulating glucose and lipid metabolism, mitochondrial function, inflammation, and interorgan communication. Despite substantial advances, the heterogeneous nature of myokine biology and their differential roles across exercise modalities remain incompletely characterized. Methods: This review critically evaluates the current evidence on exercise-induced myokines within an evidence-based framework considering mechanistic support and translational relevance. Major myokines including interleukin-۶ (IL-۶), irisin, myostatin, FGF۲۱, apelin, and BDNF are systematically analyzed based on their receptor definition, human causal evidence, and therapeutic potential. Evidence from human intervention studies, animal models, and cell-based research is synthesized. Results: The evidence demonstrates that myokines act through distinct signaling pathways—IL-۶ via IL-۶Rα/gp۱۳۰ receptor complex, irisin through integrin receptors, and FGF۲۱ via FGFR۱/β-Klotho—to mediate muscle-organ crosstalk. IL-۶ emerges as the most robust myokine with human causal evidence from tocilizumab intervention trials showing that IL-۶ signaling contributes to exercise-induced metabolic benefits. The findings reveal substantial heterogeneity in causal evidence, receptor certainty, and translational readiness across myokine axes. Conclusion: Exercise-induced myokines represent a biologically heterogeneous group of mediators of muscle-organ communication. These insights support a more selective view of myokine pathways and provide a framework for mechanism-based therapeutic development in metabolic disease.
