Methylome-proteome integration after late-life voluntary exercise training reveals regulation and target information for improved skeletal muscle health.

IF 4.7 2区 医学 Q1 NEUROSCIENCES Journal of Physiology-London Pub Date : 2025-01-01 Epub Date: 2024-07-26 DOI:10.1113/JP286681
Toby L Chambers, Andrea Dimet-Wiley, Alexander R Keeble, Amin Haghani, Wen-Juo Lo, Gyumin Kang, Robert Brooke, Steve Horvath, Christopher S Fry, Stanley J Watowich, Yuan Wen, Kevin A Murach
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Abstract

Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance-resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22-24 months of age). In this investigation, we leveraged pan-mammalian DNA methylome arrays and tandem mass-spectrometry proteomics in skeletal muscle to provide detailed information on late-life PoWeR adaptations in female mice relative to age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well as Nr4a3, Hes1 and Hox genes after PoWeR. Using a holistic method of -omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise - all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome-proteome landscape, corroborating prior late-life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. KEY POINTS: Late-life combined endurance-resistance exercise training from 22-24 months of age in mice is shown to improve molecular, biochemical, cellular and in vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7-10 per group and analysis). Multi-omics integration predicted epigenetic regulation of serine β-lactamase-like protein (LACTB - linked to tumour resistance in muscle), mind bomb 1 (MIB1 - linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N-recognin 4 (UBR4 - linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late-life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) was associated to in vivo muscle fatigue resistance.

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晚年自愿运动训练后的甲基组-蛋白质组整合揭示了改善骨骼肌健康的调节和目标信息。
运动是对抗骨骼肌老化的有效刺激。为了在临床前环境中研究运动对肌肉的影响,我们为小鼠开发了一种称为渐进负重轮跑(PoWeR)的组合耐力-阻力训练刺激。PoWeR 可改善骨骼肌的分子、生化、细胞和功能特性,并在小鼠晚期(22-24 个月)进行时促进部分表观遗传重编程。在这项研究中,我们利用泛哺乳动物 DNA 甲基组阵列和骨骼肌串联质谱蛋白质组学,提供了雌性小鼠相对于年龄匹配的静坐对照组(每组 7-10 只)的晚期 PoWeR 适应性的详细信息。PoWeR后,保守启动子位点的CpG甲基化差异与转录调控基因以及Nr4a3、Hes1和Hox基因有关。利用一种名为 "结合与表达目标分析(BETA)"的整体组学整合方法,甲基组变化与 PoWeR 后全球和线粒体翻译相关蛋白质的上调有关(P = 0.03)。具体来说,BETA 与训练后核糖体、核小体和线粒体复合体 I 蛋白丰度的甲基化控制有关。DNA 甲基化还可能影响运动后 LACTB、MIB1 和 UBR4 蛋白的诱导--所有这些都与肌肉健康有机理联系。计算序列分析预测,包括 MYC 在内的多个转录因子是运动训练甲基化组-蛋白质组格局的调节因子,这与之前的晚期 PoWeR 转录组数据相吻合。将蛋白质组与肌肉质量和抗疲劳性相关联,发现分别与 VPS13A 和 NPL 水平呈正相关。我们的研究结果揭示了 PoWeR 后与翻译调控相关的不同表观遗传和蛋白质组适应性,这可能会影响老年小鼠的骨骼肌质量和功能。关键点:小鼠从 22-24 个月大开始的晚期联合耐力-阻力运动训练可改善骨骼肌的分子、生化、细胞和体内功能特征,并促进部分表观遗传重编程和表观遗传年龄缓解。利用保守位点(也包含甲基化老化时钟位点)将 DNA CpG 36k 甲基化阵列与骨骼肌中的探索性蛋白质组学相结合,扩展了我们之前的工作,并揭示了在相当规模的雌性小鼠队列(每组 7-10 只,每项分析)中进行联合自愿运动训练后,核糖体、翻译起始、线粒体核糖体(mitoribosomal)和复合体 I 蛋白的协调和广泛调控。多组学整合预测了训练后丝氨酸β-内酰胺酶样蛋白(LACTB--与肌肉抗肿瘤有关)、心灵炸弹1(MIB1--与卫星细胞和2型纤维维持有关)和泛素蛋白连接酶E3元件N-识别素4(UBR4--与肌肉蛋白质量控制有关)的表观遗传调控。计算序列分析发现,MYC是晚年训练蛋白质组的调节因子,这与之前的转录分析结果一致。空泡蛋白分选13同源物A(VPS13A)与肌肉质量呈正相关,糖蛋白/糖脂相关的酰化酶N-乙酰神经氨酸丙酮酸裂解酶(NPL)与体内肌肉抗疲劳性相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Physiology-London
Journal of Physiology-London 医学-神经科学
CiteScore
9.70
自引率
7.30%
发文量
817
审稿时长
2 months
期刊介绍: The Journal of Physiology publishes full-length original Research Papers and Techniques for Physiology, which are short papers aimed at disseminating new techniques for physiological research. Articles solicited by the Editorial Board include Perspectives, Symposium Reports and Topical Reviews, which highlight areas of special physiological interest. CrossTalk articles are short editorial-style invited articles framing a debate between experts in the field on controversial topics. Letters to the Editor and Journal Club articles are also published. All categories of papers are subjected to peer reivew. The Journal of Physiology welcomes submitted research papers in all areas of physiology. Authors should present original work that illustrates new physiological principles or mechanisms. Papers on work at the molecular level, at the level of the cell membrane, single cells, tissues or organs and on systems physiology are all acceptable. Theoretical papers and papers that use computational models to further our understanding of physiological processes will be considered if based on experimentally derived data and if the hypothesis advanced is directly amenable to experimental testing. While emphasis is on human and mammalian physiology, work on lower vertebrate or invertebrate preparations may be suitable if it furthers the understanding of the functioning of other organisms including mammals.
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