Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia.
Institute of Nutrition and Health Sciences, Deakin University, Melbourne, Victoria, Australia.
FASEB J. 2023 Oct;37(10):e23184. doi: 10.1096/fj.202300840RR.
Exercise is a major beneficial contributor to muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple molecular layers (i.e., epigenome, transcriptome, and proteome). Identifying robust, across-molecular level targets associated with exercise response, at both group and individual levels, is paramount to develop health guidelines and targeted health interventions. Sixteen, apparently healthy, moderately trained (VO max = 51.0 ± 10.6 mL min kg ) males (age range = 18-45 years) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a longitudinal study composed of 12-week high-intensity interval training (HIIT) intervention. Vastus lateralis muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. DNA methylation (850 CpG sites) and proteomic (3000 proteins) analyses were conducted at all time points. Mixed models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. A total of 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst methylome overall shifted with training only one differentially methylated position (DMP) was significant (adj.p-value < .05). K-means analysis revealed cumulative protein changes by clusters of proteins that presented similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had large effect-sizes >0.5, among them are two novel exercise-related proteins, LYRM7 and EPN1. Integration analysis showed bidirectional relationships between the methylome and proteome. We showed a significant influence of HIIT on the epigenome and more so on the proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of these proteins in response to exercise.
运动是肌肉代谢的主要有益因素，运动带来的健康益处是多个分子层面（即表观基因组、转录组和蛋白质组）发生分子变化的结果。在群体和个体水平上，确定与运动反应相关的稳健的跨分子水平靶点对于制定健康指南和有针对性的健康干预措施至关重要。来自 Gene SMART（骨骼肌对训练的适应性反应）研究的 16 名健康、适度训练的男性（VO max=51.0±10.6mL·min-1·kg-1，年龄范围 18-45 岁）完成了一项由 12 周高强度间歇训练（HIIT）组成的纵向研究。在 HIIT 干预的 4、8 和 12 周后，收集股外侧肌活检。在所有时间点进行 DNA 甲基化（850 个 CpG 位点）和蛋白质组学（3000 种蛋白质）分析。应用混合模型估计群体和个体变化，并使用 mixOmics 包中的整体多层次方法进行甲基组和蛋白质组整合。共有 461 种蛋白质随时间显著变化（在 4、8 和 12 周时），而甲基组在训练时仅发生了一个差异甲基化位置（DMP）的变化是显著的（调整后的 p 值<.05）。K-means 分析显示，随着时间的推移，蛋白质的累积变化由具有相似变化的蛋白质簇聚类。在 101 种蛋白质中观察到个体对训练的反应。其中 7 种蛋白质的效应大小>0.5，包括两种新的与运动相关的蛋白质 LYRM7 和 EPN1。整合分析显示甲基组和蛋白质组之间存在双向关系。我们表明 HIIT 对人类肌肉的表观基因组有显著影响，对蛋白质组的影响更大，并揭示了根据运动干预中相似模式聚类的蛋白质组群。在蛋白质组中观察到个体对运动的反应，有新的线粒体和代谢蛋白在个体之间持续变化。需要进一步的研究来阐明这些蛋白质在运动反应中的作用。
