Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise
Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise
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DOI：
10.1113/jp281244
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发表时间：
2021-06-03
影响因子：
5.5
通讯作者：
von Walden, Ferdinand
中科院分区：
文献类型：
--
作者：
Figueiredo, Vandre C.;Wen, Yuan;von Walden, Ferdinand
关键点核糖体生物合成和MYC转录与急性抗阻运动（RE）相关，并在整个24小时恢复过程中与人类骨骼肌的耐力运动不同。通过全基因组测序验证了拷贝数估计，并揭示了rDNA剂量与响应RE的核糖体生物合成呈正相关。在增强子、基因间间隔区和非典型MYC相关区域的甲基化模式，而不是启动子。小鼠急性机械过载的肌细胞核特异性rDNA甲基化模式证实并扩展了人类RE的rDNA发现。基于rDNA基因剂量，可能存在肥大反应的遗传易感性。核糖体是蛋白质合成的大分子引擎。骨骼肌核糖体生物合成受到运动的刺激，尽管核糖体DNA（rDNA）拷贝数和甲基化对运动诱导的rDNA转录的贡献尚不清楚。为了研究运动对核糖体生物合成的遗传和表观遗传调控，对30名参与者（18名男性和12名女性; 31 +/- 8岁，25 +/- 4 kg m（-2））在休息和急性耐力后30 min，3 h，8 h和24 h进行骨骼肌活检（n = 10，45 min循环，70% V？O2 max）或抗阻运动（n = 10，4 x 7 x 2次运动）; 10名对照参与者在无运动的情况下进行活检。使用定量PCR和全基因组测序评估rDNA转录和剂量。使用massARRAY EpiTYPER研究rDNA启动子甲基化，使用简化代表性亚硫酸氢盐测序评估总体rDNA CpG甲基化。核糖体生物合成和MYC转录主要与阻力有关，但与耐力运动无关，表明在肥大过程中优先上调。与阻力运动，核糖体生物合成与rDNA基因剂量，以及增强子和非典型MYC相关领域的rDNA，但不是启动子的表观遗传变化。体内代谢RNA标记和遗传myc荧光标记的小鼠模型验证了急性肥大刺激对核糖体生物合成和Myc转录的影响，并且还证实了rDNA增强子和Myc相关甲基化改变，特别是在肌核中。本研究提供了第一个信息骨骼肌遗传和rDNA基因范围内的表观遗传调节核糖体生物合成的运动，揭示了新的作用rDNA剂量和CpG甲基化。
Key pointsRibosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery.A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE.Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter.Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans.A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage.Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 +/- 8 years, 25 +/- 4 kg m(-2)) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V?O2max) or resistance exercise (n = 10, 4 x 7 x 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.