Sperm microRNAs regulate paternal transmission of exercise capacity
In a recent study published in Cell Metabolism, a collaborative research team reported groundbreaking findings in their paper. This research provides the first evidence that sperm microRNAs act as carriers of epigenetic information, enabling the intergenerational transmission of paternal exercise capacity and metabolic health, thereby exerting profound effects on offspring development.
Throughout evolutionary history, exercise capacity has been fundamental to human survival, with our ancestors relying on sustained physical performance for hunting, migration, and predator evasion. However, with the advent of modern society, human lifestyles have undergone dramatic changes. Sedentary behavior and physical inactivity have become the norm, making exercise seem less essential for survival.
Yet, a growing body of research reveals that the biological benefits of exercise continue to profoundly influence human health. Exercise not only enhances individual physical fitness and metabolic profiles—reducing the risk of chronic diseases—but also exerts deeper effects on the physiological and metabolic characteristics of future generations.
Nevertheless, the mechanisms through which paternal exercise influences offspring phenotypes remain poorly understood.
In this study, the authors demonstrate that offspring sired by exercise-trained fathers exhibit intrinsic exercise adaptability and improved metabolic parameters compared to those from sedentary fathers.
Similarly, offspring of transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)—a key enhancer of mitochondrial function—also show improved endurance and metabolic traits, even in the absence of the inherited PGC-1α transgene.
Notably, the injection of sperm small RNAs from exercised fathers into normal zygotes reproduces exercise-trained phenotypes in the offspring at behavioral, metabolic, and molecular levels.
Mechanistically, both exercise training and muscular PGC-1α overexpression remodel the sperm microRNA profile, 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 establishes a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in mediating the transmission of exercise-induced phenotypes and metabolic adaptations to offspring.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00388-2
