Comment on: “Paternal Exercise Confers Endurance Capacity to Offspring Through Sperm MicroRNAs”

Recent research has presented evidence that exercise-induced benefits can be heritable and preventive of physical inactivity as well as chronic diseases in offspring. Most studies to date have focused on the benefits surrounding maternal exercise, including exercise before and during pregnancy. Benefits may also be conferred from paternal sources through sperm via small RNAs (sRNAs), which have been shown to regulate embryonic gene expression that affects the physiology and behavior of offspring. This study was designed to assess whether paternal exercise can affect sRNA profiles, such as microRNAs (miRNAs), in sperm that improve physical performance and outcomes in offspring. This study used mouse models to demonstrate differences in miRNA and gene expression. Mice were randomized to exercise training or a sedentary lifestyle for 8 weeks; overall, the exercise group had lower body weight, higher lean mass, lower fat mass, and improved femoral bone mineral density compared with the sedentary group. Open-field tests showed no significant differences in cognition or physical ability, and indirect calorimetry showed increased oxygen consumption and energy expenditure in the exercise group compared with the sedentary group. Mice were bred and exercise tests were performed on adult male offspring. Both groups showed normal growth of offspring, but the offspring of the exercise group showed increased lean mass, reduced fat mass, and improved bone mineral density, similar to the previous generation. In addition, the offspring of the exercise group showed increased duration and distance on exercise tests when compared with the offspring of the sedentary group, indicating a better aerobic capacity and metabolic profile even without exercise training. Genetically, genes associated with mitochondrial biogenesis and function were upregulated in the exercise group, along with increased expression of several associated proteins. These additionally showed specificity to muscle type, with greater effects shown in the gastrocnemius muscle compared with the plantaris muscle. Further study was attempted through the overexpression of a muscle-specific PGC-1α; offspring of mice with this genetic variation showed normal development and body weight as well as increased lean mass and decreased fat mass compared with wild-type offspring. Analysis of other genetic and behavioral factors in these mice showed possibly sex-specific mechanisms as well as overall higher expression of genes involved in mitochondrial biogenesis and function, similar to those seen by the original exercise group. A study of further generations of offspring showed that the benefits conferred by paternal exercise training were not perpetuated to the second generation. Upon deeper examination of the mechanisms surrounding paternal transmission of benefits to offspring, results showed that miRNAs are changed significantly by exercise training and can thus transfer characteristics to oocytes during fertilization. This was confirmed by the injection of altered miRNA into zygotes that conferred similar high endurance to offspring without the added factor of paternal exercise training. These results show that paternal PGC-1α, miRNAs, and other genes mediate the heritability of exercise-induced metabolic advantages and adaptations. Future research should focus on how the downregulation of embryonic genes and proteins leads to lasting alterations of phenotypic and metabolic nature in adult offspring. In addition, future studies should attempt to evaluate if exercise-induced sperm miRNAs have extra-muscular effects, if sex-specific mechanisms are present, and what sex-specific mechanisms of paternal exercise may affect in long-term phenotype and metabolism. (Summarized from Yin X, Anwar A, Yan L, et al. Paternal exercise confers endurance capacity to offspring through sperm microRNAs. Cell Metab. 2025;37:2167–2184.e8. doi: 10.1016/j.cmet.2025.09.003)