IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Pernille Hojman, Camilla Brolin, Nynne Nørgaard-Christensen, Christine Dethlefsen, Britt Lauenborg, Cecilie Køllner Olsen, Mette Marie Åbom, Thomas Krag, Julie Gehl, Bente Klarlund Pedersen

IL-6 is secreted from muscles to the circulation during high-intensity and long-duration exercise, where muscle-derived IL-6 works as an energy sensor to increase release of energy substrates from liver and adipose tissues. We investigated the mechanism involved in the exercise-mediated surge in IL-6 during exercise. Using interval-based cycling in healthy young men, swimming exercise in mice, and electrical stimulation of primary human muscle cells, we explored the role of lactate production in muscular IL-6 release during exercise. First, we observed a tight correlation between lactate production and IL-6 release during both strenuous bicycling and electrically stimulated muscle cell cultures. In mice, intramuscular injection of lactate mimicked the exercise-dependent release of IL-6, and pH buffering of lactate production during exercise attenuated IL-6 secretion. Next, we used in vivo bioimaging to demonstrate that intrinsic intramuscular proteases were activated in mice during swimming, and that blockade of protease activity blunted swimming-induced IL-6 release in mice. Last, intramuscular injection of the protease hyaluronidase resulted in dramatic increases in serum IL-6 in mice, and immunohistochemical analyses showed that intramuscular lactate and hyaluronidase injections led to release of IL-6-containing intramyocellular vesicles. We identified a pool of IL-6 located within vesicles of skeletal muscle fibers, which could be readily secreted upon protease activity. This protease-dependent release of IL-6 was initiated by lactate production, linking training intensity and lactate production to IL-6 release during strenuous exercise.

OriginalsprogEngelsk
TidsskriftAmerican journal of physiology. Endocrinology and metabolism
Vol/bind316
Udgave nummer5
Sider (fra-til)E940-E947
ISSN0193-1849
DOI
StatusUdgivet - 1 maj 2019

ID: 223974000