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The local–systemic axis of the skeletal muscle secretome
Exercise stimulates the release of bioactive factors, termed exerkines, that contribute to local and systemic adaptation. Circulating exerkines are often interpreted as direct readouts of muscle secretion, overlooking regulatory processes within tissues that shape their production, transformation, and release. Using skeletal muscle and endurance exercise as a model system, we define a local–systemic secretome axis shaped by spatial organization, stimulus-specific programs, temporal dynamics, extracellular processing, and paracrine circuitry. By integrating evidence from recent transcriptomics, proteomics, interstitial fluid, and extracellular vesicle studies, we outline how these processes govern signal propagation from muscle to circulation and inform the interpretation of circulating exerkines as biomarkers and therapeutic targets.
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