Paternal exercise as an epigenetic legacy: Sperm microRNAs bridge intergenerational metabolic health

Paternal exercise has been shown to improve offspring metabolic health, but the underlying epigenetic mechanisms remain incompletely understood. This perspective highlights a defined molecular pathway through which paternal physical activity influences offspring phenotype. Using murine models, researchers demonstrated that endurance training in male mice induces upregulation of specific microRNAs in sperm. These miRNAs are delivered to the oocyte upon fertilization and suppress the embryonic expression of Nuclear Receptor Corepressor 1 (NCoR1), a transcriptional regulator that represses oxidative metabolism. This suppression enhances mitochondrial biogenesis, promotes oxidative muscle fiber formation, and improves systemic glucose homeostasis in offspring. The identified PGC-1α–sperm miRNA–embryonic NCoR1 axis provides a mechanistic basis for the intergenerational inheritance of acquired metabolic traits. These findings position sperm as a dynamic carrier of paternal environmental information and underscore the importance of paternal preconception health in shaping offspring metabolic resilience, offering novel insights for preventive strategies against metabolic diseases.