Thomis, M. | bioRxiv Science

bioRxiv2020

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

Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate < 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).

genetics↗

bioRxiv2020

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

BackgroundThe interaction between the muscle methylome and transcriptome is understudied during ageing and periods of resistance training in young, but especially older adults. In addition, more information is needed on the role of retained methylome training adaptations in muscle memory to understand muscle phenotypical and molecular restoration after inactivity or disuse. MethodsWe measured CpG methylation (microarray) and RNA expression (RNA sequencing) in young (n = 5; age = 22 {+/-} 2 yrs) and older (n = 6; age = 65 {+/-} 5 yrs) vastus lateralis muscle samples, taken at baseline, after 12 weeks of resistance training, after training interruption (2 weeks of leg immobilization in young men, 12 weeks of detraining in older men) and after 12 weeks of retraining to identify muscle memory-related adaptations and rejuvenating effects of training. ResultsWe report that of the 427 differentially expressed genes with advanced age, 71 % contained differentially methylated (dm)CpGs in older versus young muscle. The more dmCpGs within a gene, the clearer the inverse methylation-expression relationship. Around 73 % of the age-related dmCpGs approached younger methylation levels when older muscle was trained for 12 weeks. A second resistance training period after training cessation increased the number of hypomethylated CpGs and upregulated genes in both young and older muscle. We found indication for an epi-memory within pro-proliferating AMOTL1 in young muscle and mechanosensing-related VCL in older muscle. For the first time, we integrate muscle methylome and transcriptome data in relation to both ageing and training/inactivity-induced responses and identify focal adhesion as an important pathway herein. ConclusionPreviously trained muscle is more responsive to training than untrained muscle at methylome and transcriptome level and recurrent resistance training can partially restore ageing-induced methylome alterations.

genomics↗