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Human skeletal muscle displays an epigenetic memory of resistance exercise induced-hypertrophy. It is unknown, however, whether high-intensity interval training (HIIT) also evokes an epigenetic muscle memory. This study used repeated training intervention interspersed with a detraining period to assess epigenetic memory of HIIT. Twenty healthy subjects (25 ± 5 yr) completed two HIIT interventions (training and retraining) lasting 2 mo, separated by 3 mo of detraining. Measurements at baseline, after training, detraining, and retraining included maximal oxygen consumption (V̇ o 2max). Vastus lateralis biopsies were taken for genome-wide DNA methylation and targeted gene expression analyses. V̇ o 2max improved during training and retraining (P < 0.001) without differences between interventions (P > 0.58). Thousands of differentially methylated positions (DMPs) predominantly demonstrated a hypomethylated state after training, retained even after 3-mo of exercise cessation and into retraining. Five genes, ADAM19, INPP5a, MTHFD1L, CAPN2, and SLC16A3, possessed differentially methylated regions (DMRs) with retained hypomethylated memory profiles and increased gene expression. The retained hypomethylation during detraining was associated with an enhancement in expression of the same genes even after 3 mo of detraining. SLC16A3, INPP5a, and CAPN2 are involved in lactate transport and calcium signaling. Despite similar physiological adaptations between training and retraining, memory profiles were found at epigenetic and gene expression level, characterized by retained hypomethylation and increased gene expression after training into long-term detraining and retraining. These genes were associated with calcium signaling and lactate transport. Although significant memory was not observed in physiological parameters, our novel findings indicate that human skeletal muscle possesses an epigenetic memory of HIIT. NEW & NOTEWORTHY: Cells possess a "memory" such that adaptations can be more quickly regained when a previously encountered challenge is reintroduced. Exercise provides an excellent experimental model to explore the concept of cellular memory to physiologically relevant stressors in humans. This study highlights molecular mechanisms that contribute to muscle memory in response to high-intensity interval training in humans, showing retention of DNA methylation and gene expression profiles from earlier training into detraining and retraining. [ABSTRACT FROM AUTHOR]