Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance

Regular exercise training preserves systemic homeostasis via coordinated multi-organ interactions, with skeletal muscle emerging as a pivotal effector organ and integrative signaling nexus. Recent breakthroughs in research have established the endocrine organ properties of skeletal muscle. Through contraction-induced release of myokines, skeletal muscle employs multimodal signaling mechanisms including autocrine, paracrine, and endocrine pathways, systematically elucidating the molecular basis of exercise benefits. This review innovatively proposes the “Myokine-mediated Multi-organ Metabolic Network” theory, comprehensively summarizing the role of myokines in mediating inter-organ crosstalk and dynamic communication mechanisms. These interactions involve skeletal muscle itself and multiple vital organs including heart, liver, lung, kidney, pancreas, brain, bone, skin, oral cavity, adipose tissue, intestine, stomach, mammary glands, ovaries, and prostate. Mechanistic insights elucidate that myokines function as pleiotropic signaling modulators, orchestrating multifaceted regulatory programs across six interconnected biological axes, including energy substrate flux and mitochondrial biogenesis, osteogenic differentiation and extracellular matrix remodeling, neuroplasticity and Blood-brain barrier (BBB) homeostasis, gut microbiota modulation, vascular endothelial function, and immunometabolic reprogramming within neoplastic niches. Notably, the multi-target regulatory capacity of myokines provides mechanistic insights into exercise-induced disease resistance. As “exercise-mimetic molecules,” targeted delivery strategies of myokines provide novel therapeutic directions for metabolic diseases, neurodegenerative disorders, and cancer treatment. Crucially, three research frontiers demand prioritization: decoding spatiotemporal myokine secretion patterns; mapping receptor-ligand interaction networks across organs; and developing computational models predicting system-level responses to myokine modulation. Addressing these challenges will catalyze the translation of exercise physiology discoveries into precision therapeutics.