Sperm microRNAs: Key regulators of the paternal transmission of exercise capacity

In a recent study published in Cell Metabolism, a collaborative research team led by Chen-Yu Zhang, Xi Chen, and Di-Jun Chen from Nanjing University, together with Tao Zhang from Nanjing Medical University, reported groundbreaking findings in their paper entitled “Paternal exercise confers endurance capacity to offspring through sperm microRNAs.” 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.

The scientific significance of these findings is highlighted below:

(1) Elucidating the Molecular Mechanism of Exercise-Induced Phenotype Inheritance. After fertilization, sperm microRNAs target NCoR1 in early embryos, resetting gene regulatory networks and reprogramming embryonic development. This initiates a “butterfly effect” that ultimately reshapes offspring phenotypes. Within this framework, paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 form a coherent molecular pathway through which exercise-induced endurance and metabolic adaptation are transmitted to the next generation via an intergenerational regulatory axis.

(2) Expanding the Role of MicroRNAs: From Intraspecies and Interspecies Signaling to Intergenerational Communication. MicroRNAs are recognized as mobile signaling molecules that mediate communication between cells, tissues, and even across species. This study reveals that sperm microRNAs also facilitate crosstalk across generations. These findings broaden the understanding of microRNA functions and suggest that life experiences and environmental exposures can be encoded in sperm microRNAs as epigenetic information, enabling cross-generational communication.

(3) Contributing to Improved Health and Fitness in the Next Generation. In an era where physical inactivity and sedentary lifestyles are associated with increased risks of obesity and chronic diseases, this study demonstrates that paternal exercise can enhance glucose homeostasis in offspring by promoting glucose uptake in skeletal muscle. These results underscore the importance of paternal exercise prior to conception, offering a rational and cost-effective strategy to improve the health of future generations and help break the cycle of intergenerational obesity and chronic disease.

Reference:

Yin et al. Paternal exercise confers endurance capacity to offspring through sperm microRNAs. Cell Metabolism. 6 October, 2025.

Author contact: Dr. Xi Chen. Email: xichen@nju.edu.cn.

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