Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity [RRBS]
Skeletal muscle can undergo large transcriptional changes in response to environmental stimuli such as diet or exercise in order to adapt to energetic demands. This remodelling has been associated with changes in muscle DNA methylation potentially regulating gene transcription. Despite abundant evidence that environmental stimuli can alter muscle DNA methylation, the mechanisms by which DNA methylation machinery respond to these stimuli and whether these have a physiological impact is still unclear. Therefore, we decided to investigate the importance of de novo DNA methylation on muscle methylation and function. We generated muscle specific DNMT3a knockout mice (mDKO) and investigated the impact of ablating DNMT3a in muscle on muscle DNA methylation, exercise capacity and energy metabolism. Loss of DNMT3a reduced DNA methylation in muscle over multiple genomic contexts and altered the transcription of genes known to be influenced by DNA methylation. However, mDKO mice had a similar exercise capacity and whole-body energy metabolism as WT mice. Similarly, loss of DNMT3a did not alter muscle mitochondrial function or the transcriptional response to exercise however did increase the expression of genes involved in muscle development. These data suggest that DNMT3a does not have a large role in the function of mature muscle although a role in muscle development and differentiation is still likely. Overall design: Reduced Representation Bisulfite Sequencing (RRBS) of Mus musculus soleus muscle in wild-type (WT) and DNMT3a knockout (KO), before (Bas) 10 minutes (10), 30 minutes (30) and 60 minutes (60) after exercise.