Loro Emanuele, Jang Cholsoon, Quinn William J, Baur Joseph A, Arany Zoltan P, Khurana Tejvir S
Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Department of Chemistry, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, United States.
Front Physiol. 2019 Nov 26;10:1439. doi: 10.3389/fphys.2019.01439. eCollection 2019.
Lack of interleukin 15 receptor alpha (IL15RA) increases spontaneous activity, exercise capacity and protects from diet-induced obesity by enhancing muscle energy metabolism, suggesting a role as exercise mimetic for IL15RA antagonists. Using controlled muscle stimulation mimicking moderate exercise in normal and Il15ra mice, we mapped and contrasted the metabolic pathways activated upon stimulation or deletion of IL15RA. Stimulation caused the differential regulation of 123 out of the 321 detected metabolites (FDR ≤ 0.05 and fold change ≥ ±1.5). The main energy pathways activated were fatty acid oxidation, nucleotide metabolism, and anaplerotic reactions. Notably, resting Il15ra muscles were primed in a semi-exercised state, characterized by higher pool sizes of fatty acids oxidized to support muscle activity. These studies identify the role of IL15RA in the system-wide metabolic response to exercise and should enable translational studies to harness the potential of IL15RA blockade as a novel exercise mimetic strategy.
白细胞介素15受体α（IL15RA）的缺失会增加自发活动、运动能力，并通过增强肌肉能量代谢来预防饮食诱导的肥胖，这表明IL15RA拮抗剂具有运动模拟作用。利用可控的肌肉刺激在正常小鼠和Il15ra小鼠中模拟适度运动，我们绘制并对比了刺激或缺失IL15RA后激活的代谢途径。刺激导致在检测到的321种代谢物中有123种出现差异调节（FDR≤0.05且变化倍数≥±1.5）。激活的主要能量途径是脂肪酸氧化、核苷酸代谢和回补反应。值得注意的是，静息的Il15ra肌肉处于半运动状态，其特征是用于支持肌肉活动的氧化脂肪酸库容量更大。这些研究确定了IL15RA在全系统运动代谢反应中的作用，并应能推动转化研究，以利用IL15RA阻断作为一种新型运动模拟策略的潜力。
