The Myokine Landscape: Sources, Signaling, and Context-Dependent Actions

In addition to its contractile role, skeletal muscle has important secretory functions and communicates with local and distant tissues through myokines, a heterogeneous group of cytokines, chemokines, growth factors, peptides, and extracellular-matrix-associated proteins released by muscle cells. Their production is regulated by contraction, mechanical loading, energy availability, hypoxia, inflammation, injury, and mitochondrial or metabolic stress. Through autocrine, paracrine, and endocrine mechanisms, myokines influence satellite-cell activity, myogenesis, protein turnover, muscle mass, metabolism, mitochondrial function, angiogenesis, immune-cell recruitment, extracellular-matrix remodeling, and inter-organ communication. This review provides a structured overview of current knowledge on the production, regulation, and biological actions of approximately 25 major myokines, with particular emphasis on the strength of evidence supporting their classification as bona fide muscle-derived factors. We distinguish local muscle signaling from changes in circulating concentrations of uncertain tissue origin and highlight the context-dependent nature of myokine actions. The same mediator may support adaptation and repair when transiently and locally produced but contribute to inflammation, metabolic dysfunction, fibrosis, or muscle wasting when signaling is excessive, prolonged, or disease-associated. Defining cellular sources, temporal regulation, receptor availability, and interactions within the muscle secretome will be essential for clarifying physiological relevance and translating myokine biology into biomarkers and therapeutic strategies.