Interleukin-13 drives metabolic conditioning of muscle to endurance exercise

• Type of Material: Article
• Authors: Nelson Knudsen, Harvard University; Kristopher J. Stanya, Harvard University; Alexander L. Hyde, Harvard University; Mayer M. Chalom, Harvard University; Ryan K. Alexander, Harvard University; Yae-Huei Liou, Harvard University; Kyle A. Starost, Harvard University; Matthew R. Gangl, Harvard University; David Jacobi, Harvard University; Sihao Liu, Harvard University; Danesh H. Sopariwala, Harvard University; Diogo Fonseca-Pereira, Harvard University; Jun Li, Harvard University; Frank B. Hu, Harvard University; Wendy S. Garrett, Harvard University; Vihang Narkar, University of Texas Houston; Eric Ortlund, Emory University; Jonathan Kim, Emory University; Chad M. Paton, University of Georgia; Jamie A. Cooper, University of Georgia; Chih-Hao Lee, Harvard University
• Language: English
• Date: 2020-05-01
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.aat3987
• Title of Journal or Parent Work: Science
• Volume: 368
• Issue: 6490
• Start Page: 488
• End Page: +
• Grant/Funding Information: Y.H.L. was supported by funds from Ministry of Science and Technology, Taiwan.; This work was supported by grants from NIH (F31DK107256 to N.H.K.; F31GM117854 to R.K.A.; R01DK113791 and R21AI131659 to C.H.L) and American Heart Association (16GRNT31460005 to C.H.L.).
• Keywords: Err-alpha; Receptor-alpha; Skeletal-muscle; Gamma; Science & Technology; Multidisciplinary Sciences; IL-6; Science & Technology - Other Topics; Mice; Capacity
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Nutrition; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand—an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training–mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13–/– mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Ra1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.