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Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts

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  • Subrata Chowdhury
  • Logan Schulz
  • Biagio Palmisano
  • Parminder Singh
  • Julian M Berger
  • Vijay K Yadav
  • Paula Mera
  • Helga Ellingsgaard
  • Juan Hidalgo
  • Jens Brüning
  • Gerard Karsenty
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Given the numerous health benefits of exercise, understanding how exercise capacity is regulated is a question of paramount importance. Circulating interleukin 6 (IL-6) levels surge during exercise and IL-6 favors exercise capacity. However, neither the cellular origin of circulating IL-6 during exercise nor the means by which this cytokine enhances exercise capacity has been formally established yet. Here we show through genetic means that the majority of circulating IL-6 detectable during exercise originates from muscle and that to increase exercise capacity, IL-6 must signal in osteoblasts to favor osteoclast differentiation and the release of bioactive osteocalcin in the general circulation. This explains why mice lacking the IL-6 receptor only in osteoblasts exhibit a deficit in exercise capacity of similar severity to the one seen in mice lacking muscle-derived IL-6 (mIL-6), and why this deficit is correctable by osteocalcin but not by IL-6. Furthermore, in agreement with the notion that IL-6 acts through osteocalcin, we demonstrate that mIL-6 promotes nutrient uptake and catabolism into myofibers during exercise in an osteocalcin-dependent manner. Finally, we show that the crosstalk between osteocalcin and IL-6 is conserved between rodents and humans. This study provides evidence that a muscle-bone-muscle endocrine axis is necessary to increase muscle function during exercise in rodents and humans.

Original languageEnglish
JournalThe Journal of clinical investigation
Volume130
Issue number6
Pages (from-to)2888-2902
Number of pages15
ISSN0021-9738
DOIs
Publication statusPublished - 1 Jun 2020

    Research areas

  • Animals, Female, Interleukin-6/genetics, Macaca mulatta, Mice, Mice, Knockout, Muscle, Skeletal/immunology, Osteoblasts/immunology, Signal Transduction/genetics

ID: 61780427