Overtraining as a Multisystem Disorder: An Inter-organ Communication Framework from Physiology to Molecular Crosstalk

Regular physical exercise promotes beneficial adaptations across multiple organ systems.However, when training loads chronically exceed recovery capacity (here defined as overtraining) the same molecular pathways mediating these adaptations become systemically dysregulated.This minireview adopts an integrative perspective to synthesize evidence on inter-organ communication disrupted by overtraining, focusing on three interconnected axes: muscle-brain, gut-microbiota-brain, and muscle-liver.Along the muscle-brain axis, systemic inflammation can compromise blood-brain barrier integrity and favors kynurenine accumulation in the central nervous system, generating oxidative stress and excitotoxicity.Muscle-derived mitochondrial vesicles also disrupt hippocampal mitochondrial dynamics, impairing synaptic energy metabolism.Along the gut-microbiota-brain axis, splanchnic hypoperfusion and dysbiosis can compromise intestinal barrier integrity, promoting endotoxemia and neuroinflammation, while converging on the kynurenine pathway overactivation.Along the muscle-liver axis, lactate-driven extracellular vesicles induce hepatocyte apoptosis and activate stellate cells, promoting liver fibrosis.Collectively, overtraining is characterized by recurrent molecular signatures, including systemic inflammation, lactate-driven signaling, and kynurenine pathway dysregulation, with the hippocampus emerging as a particularly vulnerable target.Integrative multi-omic approaches will be essential for developing reliable diagnostic tools and evidence-based training guidelines.