Extracellular ATP as a relevant mediator between skeletal muscle depolarizaition and interleukin‐6 expression: from cell culture to whole animal adaptations (1164.10)

Interleukin‐6 (IL6) is a relevant myokine, highly expressed in skeletal muscle cells upon exercise. We have demonstrated that extracellular ATP is a relevant mediator between skeletal muscle depolarization and intracellular calcium signaling leading to gene expression. The aim of this work was analyze the role of this pathway in controlling IL6 expression, from culture cells to an animal model. In the L6 skeletal cell line overexpressing Pannexin 1, leading to a rise in ATP release at rest, IL6 expression was 2.5 fold increased. In newborn‐derived rat myotubes, IL6 expression evoked by a tetanic electrical stimulation was abolished when extracellular ATP signaling was blocked by the ectonucleotidase apyrase or by the P2Y/P2X receptors general inhibitor suramin. In myotubes and isolated mice skeletal fibers, both exogenous ATP and ADP increased IL6 expression in a concentration dependent manner. In myotubes, ATP evoked IL6 expression through a pathway involving Ca2+ and IL6 release, activating an autocrine positive loop. In a physiological model of exercise, skeletal fibers from voluntarily active mice (5 weeks voluntarily training in an exercise wheel) had an increased sensitivity to ATP for IL6 expression compared with sedentary mice; ATP sensitivity directly depended on the level of physical activity performed. Considering that increased ATP sensitivity occurs even in the absence of metabolic modifications, ATP sensitivity emerges as an early, highly sensitive marker of muscle adaptation to training. This could have an impact not only in the exercise‐dependent expression of IL‐6 but also in other physiopathological responses. Grant Funding Source : Supported by Fondecyt‐1110467‐11100454, Conicyt‐79090021, FONDAP‐15010006, ACT‐1111