Belhaj Mehdi R, Lawler Nathan G, Hawley John A, Broadhurst David I, Hoffman Nolan J, Reinke Stacey N
Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia.
Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup, WA, Australia.
Front Mol Biosci. 2022 Aug 24;9:957549. doi: 10.3389/fmolb.2022.957549. eCollection 2022.
The AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that becomes activated by exercise and binds glycogen, an important energy store required to meet exercise-induced energy demands. Disruption of AMPK-glycogen interactions in mice reduces exercise capacity and impairs whole-body metabolism. However, the mechanisms underlying these phenotypic effects at rest and following exercise are unknown. Furthermore, the plasma metabolite responses to an acute exercise challenge in mice remain largely uncharacterized. Plasma samples were collected from wild type (WT) and AMPK double knock-in (DKI) mice with disrupted AMPK-glycogen binding at rest and following 30-min submaximal treadmill running. An untargeted metabolomics approach was utilized to determine the breadth of plasma metabolite changes occurring in response to acute exercise and the effects of disrupting AMPK-glycogen binding. Relative to WT mice, DKI mice had reduced maximal running speed ( < 0.0001) concomitant with increased body mass ( < 0.01) and adiposity ( < 0.001). A total of 83 plasma metabolites were identified/annotated, with 17 metabolites significantly different ( < 0.05; FDR<0.1) in exercised (↑6; ↓11) versus rested mice, including amino acids, acylcarnitines and steroid hormones. Pantothenic acid was reduced in DKI mice versus WT. Distinct plasma metabolite profiles were observed between the rest and exercise conditions and between WT and DKI mice at rest, while metabolite profiles of both genotypes converged following exercise. These differences in metabolite profiles were primarily explained by exercise-associated increases in acylcarnitines and steroid hormones as well as decreases in amino acids and derivatives following exercise. DKI plasma showed greater decreases in amino acids following exercise versus WT. This is the first study to map mouse plasma metabolomic changes following a bout of acute exercise in WT mice and the effects of disrupting AMPK-glycogen interactions in DKI mice. Untargeted metabolomics revealed alterations in metabolite profiles between rested and exercised mice in both genotypes, and between genotypes at rest. This study has uncovered known and previously unreported plasma metabolite responses to acute exercise in WT mice, as well as greater decreases in amino acids following exercise in DKI plasma. Reduced pantothenic acid levels may contribute to differences in fuel utilization in DKI mice.
AMP激活的蛋白激酶（AMPK）是能量稳态的主要调节因子，可通过运动激活，并与糖原结合，糖原是满足运动诱导的能量需求所需的重要能量储存。小鼠中AMPK与糖原相互作用的破坏会降低运动能力并损害全身代谢。然而，这些表型效应在休息时和运动后的潜在机制尚不清楚。此外，小鼠对急性运动挑战的血浆代谢物反应在很大程度上仍未得到充分描述。从野生型（WT）和AMPK双敲入（DKI）小鼠中采集血浆样本，这些小鼠在休息时以及在30分钟次最大强度跑步机跑步后，其AMPK与糖原的结合被破坏。采用非靶向代谢组学方法来确定急性运动后血浆代谢物变化的广度以及破坏AMPK与糖原结合的影响。相对于WT小鼠，DKI小鼠的最大跑步速度降低（<0.0001），同时体重增加（<0.01）和肥胖程度增加（<0.001）。总共鉴定/注释了83种血浆代谢物，其中17种代谢物在运动小鼠（上升6种；下降11种）与休息小鼠之间存在显著差异（<0.05；FDR<0.1），包括氨基酸、酰基肉碱和类固醇激素。与WT相比，DKI小鼠中的泛酸减少。在休息和运动条件之间以及休息时的WT和DKI小鼠之间观察到不同的血浆代谢物谱，而两种基因型的代谢物谱在运动后趋同。这些代谢物谱的差异主要由运动相关的酰基肉碱和类固醇激素增加以及运动后氨基酸及其衍生物减少来解释。与WT相比，DKI血浆在运动后氨基酸下降幅度更大。这是第一项描绘WT小鼠急性运动后小鼠血浆代谢组变化以及破坏DKI小鼠中AMPK与糖原相互作用影响的研究。非靶向代谢组学揭示了两种基因型中休息和运动小鼠之间以及休息时基因型之间代谢物谱的改变。这项研究发现了WT小鼠对急性运动已知的和以前未报道的血浆代谢物反应，以及DKI血浆在运动后氨基酸下降幅度更大。泛酸水平降低可能导致DKI小鼠在燃料利用方面的差异。
