Divergent multiomic acute exercise responses reveal the impact of sex as a biological variable.

The majority of exercise physiology research has been conducted in males, resulting in a skewed biological representation of how exercise impacts the physiological system. Extrapolating male-centric physiological findings to females is not universally appropriate and may even be detrimental. Thus, addressing this imbalance and taking into consideration sex as a biological variable is mandatory for optimization of precision exercise interventions and/or regimens. Our present analysis focused on establishing multiomic profiles in young, exercise-naïve males (n = 23) and females (n = 17) at rest and following acute exercise. Sex differences were characterized at baseline and following exercise using skeletal muscle and extracellular vesicle transcriptomics, whole blood methylomics, and serum metabolomics. Sex-by-time analysis of the acute exercise response revealed notable overlap, and divergent molecular responses between males and females. An exploratory comparison of two combined exercise regimens [high-intensity tactical training (HITT) and traditional (TRAD)] was then performed using singular value decomposition, revealing latent data structures that suggest a complex dose-by-sex interaction response to exercise. These findings lay the groundwork for an understanding of key differences in responses to acute exercise exposure between sexes. This may be leveraged in designing optimal training strategies, understanding common and divergent molecular interplay guiding exercise responses, and elucidating the role of sex hormones and/or other sex-specific attributes in responses to acute and chronic exercise.NEW & NOTEWORTHY This study examined methylomics, transcriptomics, and metabolomics in circulation and/or skeletal muscle of young, healthy, exercise-naïve males and females before and after exposure to either traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found an overlapping yet considerably sex-divergent response in the molecular mechanisms activated by exercise. These findings may provide insight into optimal training strategies for adaptation when considering sex as a biological variable.