Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential

Skeletal muscle, once regarded solely as a contractile tissue, is now recognized as a dynamic endocrine organ that secretes 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. Building on our previous review published in 2018, this review synthesizes major advances in exercise-induced myokines within an evidence-based framework considering mechanistic support and translational relevance. We highlight both well-established and emerging myokines, including interleukin-6 (IL-6), irisin, myostatin, growth differentiation factor 11 (GDF11), IL-15, brain-derived neurotrophic factor (BDNF), meteorin-like (METRNL), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21 (FGF21), β-aminoisobutyric acid (BAIBA), leukemia inhibitory factor (LIF), apelin, and musclin, and discuss their roles across major target tissues including skeletal muscle, liver, adipose tissue, and bone. We also summarize natural and synthetic compounds reported to modulate myokine expression, secretion, or activity, and discuss the opportunities and current limitations of targeting myokine pathways. Although several myokine axes show therapeutic promise, the current literature indicates substantial heterogeneity in causal evidence, receptor or target certainty, and translational readiness. These insights support a more selective view of myokines as biologically heterogeneous mediators of muscle-organ crosstalk and provide a framework for mechanism-based therapeutic development in metabolic disease.