Molecular Biomarkers of Training Maladaptation: A Multi-Omics Roadmap from Functional Overreaching to Overtraining Syndrome

Exercise adaptation depends on overload that is resolved by recovery, yet the same biology becomes maladaptive when immune, endocrine, metabolic, and muscle-centered stress signals fail to normalize. Exercise-induced maladaptation represents a systems-level failure of biological resolution, with direct relevance to disease-like dysregulation. Functional overreaching, non-functional overreaching, and overtraining syndrome remain difficult to diagnose because no single biomarker provides adequate specificity, temporal stability, or clinical portability. This narrative review synthesizes human and mechanistic evidence across proteomics, transcriptomics, metabolomics, endocrine profiling, extracellular vesicles, and mitochondrial quality-control biology to define the molecular architecture most relevant to athlete monitoring. Across these layers, the most coherent signatures cluster in immune-acute-phase activation, redox-buffering strain, endocrine drift, altered substrate availability, excitation-contraction dysfunction, integrated stress-response signaling, and defects in autophagy-mitophagy and lysosomal remodeling. Three translational elements emerge from this synthesis: a systems-convergence model of recovery failure, a staged biomarker deployment hierarchy, and a provisional Recovery Failure Index. The practical priority is therefore not a solitary marker, but serial phenotype-anchored multimarker panels that connect circulating signals with muscle-centered biology and support decision-making before prolonged recovery failure becomes entrenched.