An epigenetic clock for human skeletal muscle

Abstract

Background Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan‐tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. Methods To address this, we developed a more accurate, muscle‐specific epigenetic clock based on the genome‐wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18–89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome‐wide association study of age‐associated DNA methylation patterns in skeletal muscle. Results The newly developed clock uses 200 cytosine‐phosphate–guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine‐phosphate–guanine dinucleotides of the pan‐tissue clock. The muscle clock outperformed the pan‐tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan‐tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan‐tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. Conclusions We have developed a muscle‐specific epigenetic clock that predicts age with better accuracy than the pan‐tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle‐specific biological ageing processes.

Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle

“…These overlapping dmCpGs could, therefore, be a representation of an epigenetic clock 5 common between individuals, whereas the dmCpGs uniquely found in each study represent the epigenetic drift 5 between individuals due to stochastic factors and the specific environmental conditions of the population under investigation. To test this assumption, the 2,334 overlapping dmCpGs were compared with the 200 CpGs that were recently selected to create a muscle-specific epigenetic clock 64 . We found a significant overlap of 12 CpGs (p = 2.6e-12) (Figure 3c, File S1d).…”

DNA methylation across the genome in aged human skeletal muscle tissue and stem cells: The role of HOX genes and physical activity

“…However, aged muscle also has the smallest overlap with other aged tissue types, suggesting skeletal muscle is unique in comparison with other tissues in its epigenetic aging processes 15 . Indeed, it has recently been demonstrated that the methylation status of approximately 200 CpG sites can accurately predict chronological age in skeletal muscle tissue 16 . But that this muscle 'clock' only shares 16 of these CpG's with the original 353 CpG pan-tissue Horvath clock 16,17 .…”

“…Indeed, it has recently been demonstrated that the methylation status of approximately 200 CpG sites can accurately predict chronological age in skeletal muscle tissue 16 . But that this muscle 'clock' only shares 16 of these CpG's with the original 353 CpG pan-tissue Horvath clock 16,17 . Further, using DNA methylation arrays with coverage of ~450,000 CpG sites 18 , Zykovich et al demonstrated that compared with young human skeletal muscle, aged skeletal muscle is hypermethylated across the genome.…”

Meta-analysis of genome-wide DNA methylation and integrative OMICs in human skeletal muscle

“…DNA methylation occurs at millions of CpG dinucleotides in the genome and changes considerably with age in various human tissues 6 , including skeletal muscle [7][8][9] . Age-related DNA methylation changes in skeletal muscle may be one of the molecular mechanisms underlying sarcopenia, but the full picture is fragmentary.…”

“…Thirdly, we integrated age-related methylome changes with transcriptome and proteome changes in skeletal muscle using two external, large-scale studies. Finally, we updated our skeletal muscle epigenetic clock 9 with an additional 371 samples,…”