Abstract
Transcriptome wide changes in human skeletal muscle after acute (anabolic) and chronic resistance exercise (RE) induced hypertrophy have been extensively determined in the literature. We have also recently undertaken DNA methylome analysis (850,000 + CpG sites) in human skeletal muscle after acute and chronic RE, detraining and retraining, where we identified an association between DNA methylation and epigenetic memory of exercise induced skeletal muscle hypertrophy. However, it is currently unknown as to whether all the genes identified in the transcriptome studies to date are also epigenetically regulated at the DNA level after acute, chronic or repeated RE exposure. We therefore aimed to undertake large scale bioinformatical analysis by pooling the publicly available transcriptome data after acute (110 samples) and chronic RE (181 samples) and comparing these large data sets with our genome-wide DNA methylation analysis in human skeletal muscle after acute and chronic RE, detraining and retraining. Indeed, after acute RE we identified 866 up- and 936 down-regulated genes at the expression level, with 270 (out of the 866 up-regulated) identified as being hypomethylated, and 216 (out of 936 downregulated) as hypermethylated. After chronic RE we identified 2,018 up- and 430 down-regulated genes with 592 (out of 2,018 upregulated) identified as being hypomethylated and 98 (out of 430 genes downregulated) as hypermethylated. After KEGG pathway analysis, genes associated with ‘cancer’ pathways were significantly enriched in both bioinformatic analysis of the pooled transcriptome and methylome datasets after both acute and chronic RE. This resulted in 23 (out of 69) and 28 (out of 49) upregulated and hypomethylated and 12 (out of 37) and 2 (out of 4) downregulated and hypermethylated ‘cancer’ genes following acute and chronic RE respectively. Within skeletal muscle tissue, these ‘cancer’ genes predominant functions were associated with matrix/actin structure and remodelling, mechano-transduction (e.g. PTK2/Focal Adhesion Kinase and Phospholipase D- following chronic RE), TGF-beta signalling and protein synthesis (e.g. GSK3B after acute RE). Interestingly, 51 genes were also identified to be up/downregulated in both the acute and chronic RE pooled transcriptome analysis as well as significantly hypo/hypermethylated after acute RE, chronic RE, detraining and retraining. Five genes; FLNB, MYH9, SRGAP1, SRGN, ZMIZ1 demonstrated increased gene expression in the acute and chronic RE transcriptome and also demonstrated hypomethylation in these conditions. Importantly, these 5 genes demonstrated retained hypomethylation even during detraining (following training induced hypertrophy) when exercise was ceased and lean mass returned to baseline (pre-training) levels, identifying them as genes associated with epigenetic memory in skeletal muscle. Importantly, for the first time across the transcriptome and epigenome combined, this study identifies novel differentially methylated genes associated with human skeletal muscle anabolism, hypertrophy and epigenetic memory.
Highlights
Epigenetics is the study of DNA that is modified as a result of an encounter with the environment
We demonstrated that DNA methylation signatures were retained, even when exercise ceased during detraining, following chronic resistance exercise (RE) induced hypertrophy in humans
Of the genes upregulated and hypomethylated, this equated to 355 different cytosine-guanine base pairing (CpG) sites on these 270 genes as some individual genes had more than one CpG site that was hypomethylated per gene
Summary
Epigenetics is the study of DNA that is modified as a result of an encounter with the environment. In the present study we aimed to identify if transcriptome wide gene expression changes were associated with DNA methylation of the same genes across the genome (methylome) after acute and chronic RE. We demonstrated that DNA methylation signatures ( hypomethylation) were retained, even when exercise ceased during detraining (and lean mass was returned to pre-exercise levels), following chronic RE induced hypertrophy in humans This lead to an advantageous state for these genes to be further upregulated when later retraining induced hypertrophy occurred[12]. The secondary aim of the present study was to identify if transcriptome wide gene expression changes from pooled publicly available data sets after acute and chronic RE, were associated with the methylome changes seen across the timecourse of training, detraining and retraining in our epigenetic muscle memory studies. We hypothesised that transcriptome wide changes identified in the pooled transcriptome analysis after acute and chronic RE would be associated with altered DNA methylation of some of the same genes after training, detraining and retraining
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