Interleukin-13 drives metabolic conditioning of muscle to endurance exercise

• 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
• Journal Title: Science
• Volume: Volume 368, Number 6490
• Publisher: American Association for the Advancement of Science | 2020-05-01, Pages 488-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1126/science.aat3987
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Immunology; Health Sciences, Epidemiology; Health Sciences, Nutrition
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Skeletal-muscle; Receptor-alpha; Err-alpha; Gamma; Capacity; Mice; IL-6

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.