Creatine Monohydrate Use Is Associated with Performance-Enhancing DNA Methylation Patterns

Abstract

Long-term creatine monohydrate supplementation may induce epigenetic adaptations relevant to athletic performance. We compared DNA methylation profiles (Illumina EPIC850k array) in saliva between a focus group of resistance-trained adults using creatine for 6.2 years (n = 107) and a complement group of non-creatine users (n = 243). Sixty-four CpG sites (p ≤ 0.001, X-chromosome excluded) were differentially methylated between groups. These sites mapped to 34 genes enriched in pathways of energy metabolism, muscle development, neuromuscular function, and recovery. Notably, creatine users showed hypomethylation at gene promoters for DYRK2, TLE1, CDH5, PEX10, CYP1A1, and others, suggesting upregulation of genes that promote muscle fibre differentiation, vascularization, fatty acid metabolism, and detoxification. Conversely, creatine users exhibited hypermethylation at loci within SST (somatostatin) and ACCN2 (ASIC1), which may indicate suppression of a growth-inhibitory hormone and reduced expression of acid-sensing ion channels involved in exercise-induced pain. These methylation differences align with enhanced expression of performance-beneficial genes (e.g. endothelial nitric oxide synthase NOS3, autophagy enzyme ATG4D) and silencing of detrimental factors, potentially providing an epigenetic advantage for training adaptations. Our findings suggest that chronic creatine intake is associated with an epigenetic profile conducive to improved muscular performance. This study provides novel insight into how nutrition and supplementation may modulate the epigenome to influence human athletic capacity.