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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

Original languageEnglish
JournalAmerican journal of physiology. Endocrinology and metabolism
Issue number5
Pages (from-to)E940-E947
Publication statusPublished - 1 May 2019

    Research areas

  • interleukin-6, metalloproteinase, muscle-derived factors, myokines, physical activity

ID: 223974000