Figure 1.

Diagram showing the main paracrine and dichotomic autocrine functions of the IL-6/JAK/STAT3 pathway in the pathophysiology of skeletal muscle. Skeletal muscle physiological contraction induces IL-6 release (black arrows), with paracrine effects on other organ metabolism. Upon injury or in DMD, IL-6 is released (orange arrows) following the inflammatory response and IL-6/JAK/STAT pathway promotes muscle repair by activating pro-myogenic genes (such as MyoD) that allow MuSC differentiation and fusion into new or existing myofibers. In catabolic conditions, IL-6 levels are elevated (red arrows) and induce muscle size loss, by activation of different pro-atrophic pathways in myofibers. In neurogenic atrophy, FAPs activate the IL-6/JAK/STAT pathway. In response to acute exercise, IL-6 is highly produced (blue arrows) and IL-6/JAK/STAT pathway is activated, inducing pro-proliferation and pro-fusion genes that control contribution of MuSC to myofiber growth. In the box, the IL-6/JAK/STAT3 signaling model is shown. IL-6 binds the IL-6r-Gp130 receptor complex and activates the JAK tyrosine kinases. Once activated, JAK proteins dimerize, phosphorylate, and activate their primary substrates, the STAT proteins. Phosphorylated STAT proteins dimerize and translocate to the nucleus, where they activate different target protein-coding genes.