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

Lars R Ingerslev,Eleonora Manitta,Lewin Small,Yvonne Böttcher,Rhianna C Laker,Romain Barrès,Ann N Hansen,Brendan Deeney,Philippe Couvert,Alain Carrié

doi:10.1371/journal.pgen.1009325

Abstract

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.

Highlights

Regulation of gene expression is a critical process in all cells and plays a defining role in achieving tissue- and cell-specificity, in the face of an identical genetic code
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), in muscle
We found that loss of DNMT3A reduced DNA methylation in muscle this did not lead to differences in exercise capacity or energy

Summary

Introduction

Regulation of gene expression is a critical process in all cells and plays a defining role in achieving tissue- and cell-specificity, in the face of an identical genetic code. The control of gene expression is dependent upon transcription factors which, upon activation, bind to transcription factor-specific DNA motifs in promoter and/or enhancer regions, recruit co-factors and initiate transcription. Muscle contraction results in large-scale transcriptional remodelling of metabolic, antioxidant and contractile genes which participate in the adaptation to the increased demands placed on the tissue [2]. This transcriptional remodelling is associated with changes in DNA methylation after both acute exercise [3,4,5] and exercise training [5,6,7]. Either through diabetes status [8], fasting [9], weight loss [10] or diet [7,11] have been shown to alter DNA methylation in skeletal muscle

Results

Discussion

Conclusion