Exercise Training Attenuates the Monocyte Transcriptome Response to Acute Exercise in Adolescents: Evidence for Sex-Specific Molecular Adaptations

Background: Atherosclerosis is tied to functional characteristics of circulating monocytes, the disease in adults likely begins in childhood and adolescence, and clinical heart disease differs substantially between women and men. Since monocyte function is influenced by exercise, we measured monocyte gene and noncoding RNA [ncRNA] responses to acute exercise before and after an 8-week endurance training intervention in adolescents. We identified pathways related to cardiovascular disease risk and explored sex differences in the exercise response. Methods: Twelve males and 9 females (14-17 years) completed an acute exercise protocol consisting of ten 2-min cycling bouts at 70% of maximal work rate, interspersed with 1-min rest performed before and after training intervention. Blood was collected before and immediately after each acute exercise. Peripheral blood monocytes were isolated and total RNAseq was performed. Results: Exercise training did not alter baseline (pre-acute exercise) monocyte transcriptomic profiles in either sex (FDR>0.1). Prior to training, acute exercise induced a markedly greater monocyte transcriptomic response in females compared with males (5,148 vs. 571 differentially expressed molecules, FDR < 0.1), with 315 transcripts demonstrating sex-specific responses. Pathway analyses identified vascular-function-related pathways only in males, whereas pathways related to adipose tissue crosstalk and oxidative metabolism were identified only in females. Following training, the acute transcriptomic response was markedly attenuated in both sexes (165 molecules in males and 94 in females, FDR < 0.1), representing an approximately 98% reduction in females and a ~70% reduction in males compared with pre-training responses. Twenty-six molecules exhibited sex-specific post-training response patterns, with minimal residual pathway activation. Conclusion: This study provides new insight into sex-specific monocyte transcriptomic responses to acute exercise in adolescents and demonstrates that training markedly attenuates monocyte molecular responsiveness to acute exercise. These immune adaptations may contribute to the cardioprotective effects of regular physical activity in both sexes.