From Bench to Motion: Unraveling Exercise Biology Through 3D Human Organoids

Despite extensive research, the systemic biological mechanisms underlying exercise-induced physiological adaptations remain incompletely understood. While animal models (e.g., rodents, non-human primates) have been instrumental in elucidating exercise-mediated benefits in aging and disease, interspecies differences in genomics, epigenetics, and metabolic regulation limit their translational relevance. The advent of induced pluripotent stem cell (iPSC)-derived 3D organoids revolutionizes exercise biology research by enabling human-specific modeling of tissue architecture and donor genomic/epigenetic profiles. This review highlights three transformative strategies: (1) Athlete-derived organoids preserving exercise-induced epigenetic memory to study muscle/neural adaptations; (2) Engineered systems integrating optogenetics and microfluidics to simulate mechanical forces (e.g., muscle contraction) and systemic signals (e.g., cytokines); (3) multi-omics mapping revealing exercise-responsive pathways like mitochondrial biogenesis. Collectively, these patient-specific models bridge pathophysiology with high-throughput screening, advancing precision medicine—from personalized training regimens to therapies counteracting sedentary-related diseases.