Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Metabolism. 2022 Oct;135:155268. doi: 10.1016/j.metabol.2022.155268. Epub 2022 Jul 28.
AIMS/HYPOTHESIS: Metabolic effects of exercise may partly depend on the time-of-day when exercise is performed. We tested the hypothesis that exercise timing affects the adaptations in multi-tissue metabolome and skeletal muscle proteome profiles in men with type 2 diabetes.
Men fitting the inclusion (type 2 diabetes, age 45-68 years and body mass index 23-33 kg/m) and exclusion criteria (insulin treatment, smoking, concurrent systemic disease, and regular exercise training) were included in a randomized crossover trial (n = 15). Participants included in this metabolomics and proteomics analysis fully completed all exercise sessions (n = 8). The trial consisted of two weeks of high-intensity interval training (HIT) (three sessions/week) either in the morning (08:00, n = 5) or afternoon (16:45, n = 3), a two-week wash-out period, and an additional two weeks of HIT at the opposing time. Participants and researchers were not blinded to group allocation. Blood, skeletal muscle and subcutaneous adipose tissue were obtained before the first, and after each training period. Broad-spectrum, untargeted proteomic analysis was performed on skeletal muscle, and metabolomic analysis was performed on all biosamples. Differential content was assessed by linear regression and pathway set enrichment analyses were performed. Coordinated metabolic changes across tissues were identified by Spearman correlation analysis.
Metabolic and proteomic profiles remained stable after two weeks of HIT, and individual metabolites and proteins were not altered, irrespective of the time of day at which the training was performed. However, coordinated changes in relevant metabolic pathways and protein categories were identified. Morning and afternoon HIT similarly increased plasma diacylglycerols, skeletal muscle acyl-carnitines, and subcutaneous adipose tissue sphingomyelins and lysophospholipids. Acyl-carnitines were central to training-induced metabolic cross-talk across tissues. Plasma carbohydrates, via the penthose phosphate pathway, were increased and skeletal muscle lipids were decreased after morning compared to afternoon HIT. Skeletal muscle lipoproteins were higher, and mitochondrial complex III abundance was lower after morning compared to afternoon HIT.
CONCLUSIONS/INTERPRETATION: We provide a comprehensive analysis of a multi-tissue metabolomic and skeletal muscle proteomic responses to training at different times of the day in men with type 2 diabetes. Increased circulating lipids and changes in adipose tissue lipid composition were common between morning and afternoon HIT. However, afternoon HIT increased skeletal muscle lipids and mitochondrial content to a greater degree than morning training. Thus, there is a diurnal component in the metabolomic and proteomic response to exercise in men with type 2 diabetes. The clinical relevance of this response warrants further investigation.
目的/假设：运动的代谢效应可能部分取决于运动进行的时间。我们检验了这样一个假设，即运动时间会影响 2 型糖尿病男性多组织代谢组和骨骼肌蛋白质组谱的适应性。
符合纳入（2 型糖尿病、年龄 45-68 岁和体重指数 23-33kg/m2）和排除标准（胰岛素治疗、吸烟、合并系统性疾病和规律运动训练）的男性被纳入一项随机交叉试验（n=15）。完成所有运动课程的参与者（n=8）被纳入这项代谢组学和蛋白质组学分析。该试验包括两周高强度间歇训练（HIT）（每周 3 次），分别在上午（08:00，n=5）或下午（16:45，n=3）进行，然后是两周洗脱期，最后再进行两周相反时间的 HIT。参与者和研究人员对分组分配不知情。在第一次和每次训练后，采集血液、骨骼肌和皮下脂肪组织。对骨骼肌进行广谱、非靶向蛋白质组学分析，对所有生物样本进行代谢组学分析。通过线性回归评估差异含量，并进行途径集富集分析。通过 Spearman 相关性分析确定跨组织的协调代谢变化。
HIT 两周后，代谢和蛋白质组学谱保持稳定，无论训练时间如何，个体代谢物和蛋白质均未改变。然而，确定了相关代谢途径和蛋白质类别协调变化。上午和下午的 HIT 同样增加了血浆二酰基甘油、骨骼肌酰基肉碱和皮下脂肪组织鞘磷脂和溶血磷脂。酰基肉碱是跨组织训练诱导代谢交叉对话的核心。与下午的 HIT 相比，上午的 HIT 通过戊糖磷酸途径增加了血浆碳水化合物，减少了骨骼肌脂质。上午的 HIT 后，骨骼肌脂蛋白更高，线粒体复合物 III 丰度更低。
结论/解释：我们提供了一项综合分析，研究了 2 型糖尿病男性在一天不同时间进行训练时多组织代谢组和骨骼肌蛋白质组的反应。上午和下午的 HIT 之间共同的变化是循环脂质增加和脂肪组织脂质组成的变化。然而，下午的 HIT 增加骨骼肌脂质和线粒体含量的程度大于上午的训练。因此，2 型糖尿病男性对运动的代谢组学和蛋白质组学反应存在昼夜成分。这种反应的临床意义值得进一步研究。
