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We hypothesized that\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation correlates with markers of aerobic metabolism and interacts with genotype and enzyme activity to explain interindividual variability in muscle oxidative capacity. 114 samples from healthy, physically diverse white Caucasian men (age: 29.5\u2009\u00b1\u20098.1\u2009years; weight: 76.9\u2009\u00b1\u200914.5\u2009kg) were analyzed for aerobic capacity, metabolic profiles and cellular composition of\n                    <jats:italic>m. vastus lateralis<\/jats:italic>\n                    . Molecular endpoints of the ACE system included\n                    <jats:italic>ACE<\/jats:italic>\n                    genotype, promoter methylation (23 CpG sites), mRNA expression, enzyme activity, angiotensin 2 levels, and markers of mitochondrial, glycolytic, and lipid metabolism.\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation in muscle was compared to the methylation in capillary blood from a second study group of 24 VO2max\u2010 and genotype\u2010matched male white Caucasian subjects. Statistical analyses comprised Pearson correlations, regression modeling (\u03b1\u2009=\u20090.05), network analysis, and ANOVA. Participants exhibited a wide range in VO\u2082max (2.1\u20135.4\u2009L\u00b7min\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) and\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation (0.37\u2009\u00b1\u20090.18).\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation in muscle was higher than in blood, doubling with heart rate\u2010elevating physical activity &gt;\u20096\u2009h weekly and endurance exercise (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.090 and\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.059), and was lowest in inactive, aerobically unfit\n                    <jats:italic>ACE I<\/jats:italic>\n                    \u2010allele carriers. Exercise induced significant metabolic shifts, including a rise in blood angiotensin 2 from 18.1 to 45.6\u2009pg\/mL.\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation was inversely correlated with ACE activity (r\u2009=\u2009\u22120.406), angiotensin 2 (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.447), and post\u2010exercise\n                    <jats:italic>ACE<\/jats:italic>\n                    mRNA expression (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.745), and there was an influence of the\n                    <jats:italic>ACE I\/D<\/jats:italic>\n                    gene polymorphism in interaction with the state of aerobically fitness (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.046,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.297). Regression models incorporating\n                    <jats:italic>ACE<\/jats:italic>\n                    regulatory parameters significantly explained variance in slow\u2010twitch fiber percentage and cross\u2010sectional area, mitochondrial volume density, and key lipid\/glucose metabolites (mean\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.493; power &gt;\u20090.8). Seven metabolites, including acetyl\u2010CoA, adenosine monophosphate, and phosphocreatine, displayed opposing associations with\n                    <jats:italic>ACE<\/jats:italic>\n                    genotype and methylation, indicating divergent regulatory pathways. Notably, low promoter methylation exerted pronounced effects in\n                    <jats:italic>ACE\u2010II<\/jats:italic>\n                    homozygotes.\n                    <jats:italic>ACE<\/jats:italic>\n                    promoter methylation, integrated with other regulatory indexes of the ACE system, contributes to the slow aerobic muscle phenotype and its metabolic response to endurance exercise. Low\n                    <jats:italic>ACE<\/jats:italic>\n                    \u2010promoter methylation may override I\u2010allele\u2013driven transcriptional silencing, offering a novel marker of individual training adaptation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202504082r","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:54:27Z","timestamp":1773827667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic Modulation of the\n                    <scp>ACE<\/scp>\n                    System Underlies the Slow Aerobic Muscle Phenotype and Metabolic Exercise Response"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0479-7243","authenticated-orcid":false,"given":"Fl\u00fcck","family":"Martin","sequence":"first","affiliation":[{"name":"Swiss Federal Institute of Sport Magglingen SFISM  Magglingen 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