Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts
Subrata Chowdhury, … , Jens Brüning, Gerard Karsenty
Subrata Chowdhury, … , Jens Brüning, Gerard Karsenty
Published February 20, 2020
Citation Information: J Clin Invest. 2020;130(6):2888-2902. https://doi.org/10.1172/JCI133572.
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Research Article Bone biology Article has an altmetric score of 43

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

Abstract

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.

Authors

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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Figure 1

IL-6 is necessary for the increase in circulating osteocalcin levels observed in response to a training intervention in humans.

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IL-6 is necessary for the increase in circulating osteocalcin levels obs...
(A–C) Circulating IL-6 levels in (A) rhesus monkeys (14 ± 0.8 years old), (B) rats (4 months old), and (C) mice (3 months old) treated with vehicle or osteocalcin (Ocn) (13.5 ng/g for monkeys, 30 ng/g for rats, and 30 ng/g for mice). n = 12 per treatment. Statistical analyses were conducted using 1-way ANOVA followed by Tukey’s post hoc test (A) or 2-tailed unpaired t test (B and C). (D) Circulating uncarboxylated and bioactive Ocn levels in obese, nondiabetic subjects treated with either placebo or a neutralizing antibody against the IL-6 receptor in combination with or without intensive endurance exercise for 45 minutes, 3 times a week, for 12 consecutive weeks. n = 11 per group except no exercise with the tocilizumab group, n = 12. Statistical analyses were conducted using 1-way ANOVA followed by the Holm-Sidak post hoc test. All results presented as the mean ± SEM. *P < 0.05; **P < 0.01.