Abstract
BackgroundKnowledge of age‐related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.MethodsWe conducted a large‐scale epigenome‐wide association study meta‐analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18–89 years old). We explored the genomic context of age‐related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age‐related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html).ResultsWe identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age‐related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate.ConclusionsWe provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open‐access, user‐friendly, web‐based tool called MetaMeth (https://sarah‐voisin.shinyapps.io/MetaMeth/).
Highlights
Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans
The CpGs associated with age at a stringent meta-analysis false discovery rate (FDR)
We identified differentially methylated regions (DMRs) using the dmrcate package, at a Fisher’s multiple comparison statistic
Summary
Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. In 2015, people lived 5 years longer than in 2000, but only 4.6 years longer in good health.[2] Ageing leads to the progressive loss of muscle mass and strength, resulting in a disorder termed sarcopenia. Sarcopenia is a serious condition leading to an increased risk of many conditions including cancer, type 2 diabetes (T2D), and cardiovascular diseases.[3] This process is driven by a host of adverse molecular changes in skeletal muscle with advancing age. Unravelling the molecular changes caused by ageing in skeletal muscle is the basic foundation for the development of drugs and targeted health-related interventions to help prevent sarcopenia and maximize healthspan
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