Effect of Interleukin-15 Receptor Alpha Ablation on the Metabolic Responses to Moderate Exercise Simulated by in vivo Isometric Muscle Contractions

Emanuele Loro; Cholsoon Jang; William J Quinn 3rd; Joseph A Baur; Zoltan P Arany; Tejvir S Khurana

doi:10.3389/fphys.2019.01439

Effect of Interleukin-15 Receptor Alpha Ablation on the Metabolic Responses to Moderate Exercise Simulated by in vivo Isometric Muscle Contractions

Front Physiol. 2019 Nov 26:10:1439. doi: 10.3389/fphys.2019.01439. eCollection 2019.

Authors

Emanuele Loro¹, Cholsoon Jang², William J Quinn 3rd³, Joseph A Baur⁴, Zoltan P Arany⁵, Tejvir S Khurana¹

Affiliations

¹ Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
² Department of Chemistry, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, United States.
³ Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
⁴ Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
⁵ Department of Medicine, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Abstract

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 in vivo 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.

Keywords: exercise; exercise mimetics; fatty acid oxidation; in vivo stimulation; interleukin-15 receptor alpha; metabolism; metabolomics; muscle.