2021,
PLOS Genetics.
DOI:
10.1371/journal.pgen.1009325
Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity
Lewin Small
, Lars R. Ingerslev
, Eleonora Manitta
, Rhianna C. Laker
, Ann N. Hansen
, Brendan Deeney
, Alain Carrié
, Philippe Couvert
, Romain Barrès
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.
Related Links:
2023-04-24 15:24:00
徐炳祥:
#paper doi: 10.1371/journal.pgen.1009325，PLOS GENETICS, 2021, Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity。早年的研究表明，运动负荷后肌纤维DNA甲基化水平发生了明显改变，然而二者之间是否存在因果关系仍未被深入研究，该研究以小鼠比目鱼肌为实验材料，研究在肌纤维特异性DNMT3A敲除后运动负荷引起的DNA甲基化、运动负荷诱导的基因表达谱重塑和运动负荷诱导后的表型变化。结果显示DNMT3A敲除诱导的全基因组去甲基化与其余诸项均无显著关联，因而认为DNA甲基化图谱的重塑仅是运动负荷诱导的基因表达重编程过程的副产品。该研究的一个明显缺陷是DNMT3A的敲除效率和由此诱导的全基因组去甲基化幅度均不足。该研究提供了运动负荷调控DNA甲基化图谱的有益信息，同时提供了合理报告阴性结果的范例。