Introduction: While life expectancy has increased over the past 15 years, the extension of healthspan—years lived in good health—has not kept pace. This disparity is expected to grow as longevity increases. Age-related conditions, such as sarcopenia and cardiovascular disease, significantly affect 16% and 70% of the population, respectively. Emerging evidence suggests that the decline of skeletal and cardiac muscles may share common triggers and outcomes, though the mechanisms behind this synergy remain poorly understood. We hypothesize that cross-talk in DNA methylation may underlie the interconnected deterioration of these muscle types.
Methods: We performed a large-scale epigenome-wide association study (EWAS) meta-analysis of age-related DNA methylation changes in human skeletal muscle (n = 1,431; ages 18 – 89) and cardiac muscle (n = 71, ages 24 - 92). We also integrated results with advanced bioinformatics methods to compare age-related changes in these tissues.
Results: We identified 131,894 CpG sites associated with ageing in skeletal muscle and 210 in cardiac muscle, with 161 sites intersecting between the two tissues. Intersection results revealed a positive correlation between skeletal muscle and cardiac tissue in almost all intersected sites. Enrichment analysis showed that these CpGs are predominantly linked to RNA and protein metabolism pathways, cellular stress responses, aerobic respiration, electron transport, antigen processing, GPCR ligand binding, viral infection pathways, and translation.
Conclusion: Our findings provide novel insights into the epigenetic cross-talk between skeletal and cardiac muscle during ageing, suggesting a shared epigenetic trigger for age-related changes. Future studies will focus on expanding cardiac tissue samples to enhance the robustness of comparative analyses and investigate the functional basis for such shared mechanisms.