Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity

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In response to physical exercise and diet, skeletal muscle adapts to energetic demands through large transcriptional changes. This remodelling is associated with changes in skeletal muscle DNA methylation which may participate in the metabolic adaptation to extracellular stimuli. Yet, the mechanisms by which muscle-borne DNA methylation machinery responds to diet and exercise and impacts muscle function are unknown. Here, we investigated the function of de novo DNA methylation in fully differentiated skeletal muscle. We generated muscle-specific DNA methyltransferase 3A (DNMT3A) knockout mice (mD3AKO) and investigated the impact of DNMT3A ablation on skeletal muscle DNA methylation, exercise capacity and energy metabolism. Loss of DNMT3A reduced DNA methylation in skeletal muscle over multiple genomic contexts and altered the transcription of genes known to be influenced by DNA methylation, but did not affect exercise capacity and whole-body energy metabolism compared to wild type mice. Loss of DNMT3A did not alter skeletal muscle mitochondrial function or the transcriptional response to exercise however did influence the expression of genes involved in muscle development. These data suggest that DNMT3A does not have a large role in the function of mature skeletal muscle although a role in muscle development and differentiation is likely.

Author summary

Skeletal muscle is a plastic tissue able to adapt to environmental stimuli such as exercise and diet in order to adapt energetic demand. One of the ways in which skeletal muscle can rapidly react to these stimuli is DNA methylation. This is when chemical groups are attached to DNA, potentially influencing the transcription of genes. We investigated the function of DNA methylation in skeletal muscle by generating mice that lacked one of the main enzymes responsible for de novo DNA methylation, DNA methyltransferase 3A (DNMT3A), specifically in muscle. We found that loss of DNMT3A reduced DNA methylation in muscle however this did not lead to differences in exercise capacity or energy metabolism. This suggests that DNMT3a is not involved in the adaptation of skeletal muscle to diet or exercise.

Original languageEnglish
Article number1009325
JournalPLOS Genetics
Issue number1
Number of pages24
Publication statusPublished - 2021

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