运动诱导的Serhl2启动子甲基化及其对大鼠骨骼肌脂质代谢的影响。

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-01 DOI:10.1016/j.molmet.2024.102081

Mutsumi Katayama , Kazuhiro Nomura , Jonathan M. Mudry , Alexander V. Chibalin , Anna Krook , Juleen R. Zierath

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引用次数: 0

摘要

目的：运动等环境因素可诱导表观遗传修饰，骨骼肌中发生运动反应性DNA甲基化变化。为了确定耐力游泳训练的骨骼肌DNA甲基化特征，我们使用了全基因组甲基化DNA免疫沉淀（MeDIP）测序。结果：差异甲基化启动子区（DMRs）基因集表达分析（GSEA）发现，运动训练大鼠骨骼肌启动子区存在差异高甲基化或低甲基化的4个基因集富集，包括与脂质代谢过程相关的基因集。单碱基分辨率亚硫酸盐测序证实，在运动训练的大鼠中，Serhl2（丝氨酸水解酶样2）转录起始位点邻近的CpGs被低甲基化。在运动训练大鼠中，以及在电脉冲刺激（EPS）下的L6肌管培养皿运动模型中，Serhl2基因表达上调。Serhl2启动子活性受甲基化调控，并响应EPS。我们在Serhl2启动子区域发现了Nr4a结合基序，该基序在删除后降低了Serhl2启动子活性，并消除了L6肌管中对甲基化的敏感性。L6肌管中Serhl2基因的沉默减少了细胞内脂质氧化和三酰基甘油合成。结论：运动训练通过表观基因组修饰丝氨酸水解酶样2促进骨骼肌细胞内脂质代谢和表型改变。Serhl2启动子的低甲基化影响Nr4a转录因子结合、Serhl2启动子活性和骨骼肌中Serhl2 mRNA的表达。我们的数据链接运动诱导的表观基因组调控Serhl2与骨骼肌脂质氧化和三酰甘油合成。

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Exercise-induced methylation of the Serhl2 promoter and implication for lipid metabolism in rat skeletal muscle

Objectives

Environmental factors such as physical activity induce epigenetic modifications, with exercise-responsive DNA methylation changes occurring in skeletal muscle. To determine the skeletal muscle DNA methylation signature of endurance swim training, we used whole-genome methylated DNA immunoprecipitation (MeDIP) sequencing.

Methods

We utilized endurance-trained rats, cultured L6 myotubes, and human skeletal muscle cells, employing MeDIP sequencing, gene silencing, and palmitate oxidation assays. Additional methods included promoter luciferase assays, fluorescence microscopy, and RNA/DNA analysis to investigate exercise-induced molecular changes.

Results

Gene set enrichment analysis (GSEA) of differentially methylated promoter regions identified an enrichment of four gene sets, including those linked to lipid metabolic processes, with hypermethylated or hypomethylated promoter regions in skeletal muscle of exercise-trained rats. Bisulfite sequencing confirmed hypomethylation of CpGs in the Serhl2 (Serine Hydrolase Like 2) transcription start site in exercise-trained rats. Serhl2 gene expression was upregulated in both exercise-trained rats and an "exercise-in-a-dish" model of L6 myotubes subjected to electrical pulse stimulation (EPS). Serhl2 promoter activity was regulated by methylation and EPS. A Nr4a binding motif in the Serhl2 promoter, when deleted, reduced promoter activity and sensitivity to methylation in L6 myotubes. Silencing Serhl2 in L6 myotubes reduced intracellular lipid oxidation and triacylglycerol synthesis in response to EPS.

Conclusions

Exercise-training enhances intracellular lipid metabolism and phenotypic changes in skeletal muscle through epigenomic modifications on Serhl2. Hypomethylation of the Serhl2 promoter influences Nr4a transcription factor binding, promoter activity, and gene expression, linking exercise-induced epigenomic regulation of Serhl2 to lipid oxidation and triacylglycerol synthesis.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.