Priority Research Paper Volume 12, Issue 12 pp 11200—11223

Figure 8. Proposal mechanism of action of ET-1 on muscular fibrosis and senescence. Myoblast cells present both type of ET-1 receptors, ET_A and ET_B, which are inhibited by specific antagonists such as BQ123 and BQ788, respectively. The binding of ET-1 to ET_A receptor induces fibrosis and senescence through ROS production by activation of PI₃K-AKT-GSK pathway. The inflammation induced by ET-1 could be also implied. Several antagonists were used to inhibit both, ROS production with the antioxidant N-acetylcysteine (NAC), and the PI₃K-AKT-GSK pathway with AKT inhibitor, LY-294,002 and Wortmannin, to check the mechanism. Fibronectin could induce senescence through integrin receptor activation by joining to RGD sequence, and then trigger some downstream pathways through ILK activation. Tirofiban blocks the joining of FN to RGD sequence. Findings in aged mice are showed below which are similar to those found in myoblast cells induced by ET-1, suggesting that the appearance of fibrosis and senescence could be involved in the genesis of sarcopenia related to aging. Note: all antagonists or inhibitors are represented in an orange box and unexplored mechanisms with an arrow with dashed pink line.