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

Abstract

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.

Effect of Ischemic Preconditioning on Marathon-Induced Changes in Serum Exerkine Levels and Inflammation

“…Hence, it could be expected that the increase in IL-10 levels would be reduced after the run; however, that was not the case, as IL-10 levels increased to the same level after the marathon in both groups of athletes. Further, exercise-induced increase in serum IL-6 levels is associated with intramuscular activation of metalloproteinases (MMP2 and MMPx); inactivation of these proteins blunts IL-6 release induced by swimming (Hojman et al, 2019). Interestingly, we here observed that the levels of TIMP-1, a tissue inhibitor of metalloproteinases, significantly decreased after the marathon and this effect was attenuated in runners after IPC.…”

Physical activity level and temporomandibular disorders in South Koreans

“…The relationship between the increased prevalence of TMD pain and moderate‐intensity exercise could partly be explained by the increased frequency of jaw‐clenching reported during intense exercise sessions and concentrating . Another mechanism may involve the increase in inflammatory cytokines following high‐intensity, long‐duration exercises . Many systematic reviews have reported on the low quality of evidence concerning the relationship between musculoskeletal disease symptoms and physical activity level.…”

The Use of Pulsed Electromagnetic Field to Modulate Inflammation and Improve Tissue Regeneration: A Review

“…IL-6 acts as both a proinflammatory cytokine and an anti-inflammatory myokine. 58,59 Skeletal muscle produces and releases significant levels of IL-6, which has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of muscle satellite cells. 59 Paradoxically, deleterious actions for IL-6 have been proposed for atrophy and muscle wasting.…”