TY - JOUR
T1 - IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity
AU - Hojman, Pernille
AU - Brolin, Camilla
AU - Nørgaard-Christensen, Nynne
AU - Dethlefsen, Christine
AU - Lauenborg, Britt
AU - Olsen, Cecilie Køllner
AU - Åbom, Mette Marie
AU - Krag, Thomas
AU - Gehl, Julie
AU - Pedersen, Bente Klarlund
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - Chemokine CXCL1/metabolism
KW - Cytokines/metabolism
KW - Electric Stimulation
KW - Exercise
KW - Humans
KW - Interleukin-10/metabolism
KW - Interleukin-1beta/metabolism
KW - Interleukin-6/metabolism
KW - Lactic Acid/metabolism
KW - Male
KW - Matrix Metalloproteinase 2/drug effects
KW - Matrix Metalloproteinase 9/drug effects
KW - Mice
KW - Muscle Fibers, Skeletal/drug effects
KW - Muscle, Skeletal/metabolism
KW - Physical Conditioning, Animal
KW - Tumor Necrosis Factor-alpha/metabolism
KW - Young Adult
KW - metalloproteinase
KW - interleukin-6
KW - muscle-derived factors
KW - myokines
KW - physical activity
U2 - 10.1152/ajpendo.00414.2018
DO - 10.1152/ajpendo.00414.2018
M3 - Article
C2 - 30779630
VL - 316
SP - E940-E947
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 5
ER -