Angiotensin-converting enzyme and exercise adaptations: Genetic variability, pharmacological modulation and future...

Individual responses to exercise training vary widely, shaping athletic performance, rehabilitation outcomes and long‑term health trajectories. This review synthesizes evidence on how angiotensin-converting enzyme (ACE) activity, influenced by genetic variation, epigenetic regulation and pharmacological modulation, shapes adaptations in skeletal muscle hypertrophy, cardiac remodelling, erythropoiesis, endurance capacity and injury susceptibility. We highlight ACE's nuanced role, showing that pharmacological inhibition selectively attenuates cardiac and haematological adaptations, such as haemoglobin mass and lean body mass, without affecting peripheral muscle adaptations and aerobic performance. Additionally, exercise itself modulates ACE expression and the broader renin-angiotensin system signalling network in a context-dependent manner, complicating genotype-phenotype interactions. Future research should move decisively beyond genotype-based stratification and prioritize direct phenotyping of ACE activity, together with comprehensive profiling of the entire renin-angiotensin system axis, as genotype alone poorly predicts enzyme levels or downstream signalling. More broadly, ACE inhibition serves as a mechanistic model for systematically investigating biological pathways underlying individual variability in training responses, advancing precision exercise medicine.