Paternal exercise confers endurance capacity to offspring through sperm microRNAs

Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring. • Paternal exercise enhances endurance capacity and metabolic health in adult offspring • Sperm microRNAs regulate embryonic NCoR1 to transmit exercise-induced phenotypes • Paternal exercise provides a cost-effective route to improve offspring health Yin et al. show that paternal exercise improves offspring endurance capacity and metabolic health via sperm microRNAs that reprogram gene expression in early embryos, revealing how exercise benefits can be inherited across generations.