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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

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

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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 9

mIL-6 favors fatty acid uptake and catabolism in myofibers during exercise through osteocalcin.

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mIL-6 favors fatty acid uptake and catabolism in myofibers during exerci...
(A and B) Circulating NEFA levels at rest and after exercise in 3-month-old Il6Hsa–/– and Il6rOsb–/– mice and their respective controls. (C–F) Expression of Fatp1 and Cpt1b at rest and after exercise in gastrocnemius of 3-month-old (C) Il6fl/fl and Il6Hsa–/– mice, (D) Il6rfl/fl versus Il6rOsb–/– mice, (E) controls (WT, Il6Hsa+/–, and Ocn+/–) versus Ocn+/– Il6Hsa+/– mice, and (F) controls (WT, Il6rOsb+/–, and Ocn+/–) versus Ocn+/– Il6rOsb+/– mice. (G–J) Western blot analysis of HSL phosphorylation (Ser563) in tibialis muscles of 3-month-old (G) Il6fl/fl versus Il6Hsa–/–, (H) Il6rfl/fl versus Il6rOsb–/–, (I) controls (WT, Il6Hsa+/–, and Ocn+/–) versus Ocn+/– Il6Hsa+/–, and (J) controls (WT, Il6rOsb+/–, and Ocn+/–) versus Ocn+/– Il6rOsb+/– mice after exercise. These results are representative of 3 independent experiments. Data in A–E were analyzed by 1-way ANOVA followed by Tukey’s post hoc test. Results presented as the mean ± SEM. *P < 0.05.

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