Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China.
PLoS One. 2012;7(4):e34081. doi: 10.1371/journal.pone.0034081. Epub 2012 Apr 4.
p38 mitogen-activated protein kinase (MAPK) is an essential kinase involved in myogenic differentiation. Although many substrates of p38 MAPK have been identified, little is known about its upstream activators during myogenic differentiation. TRAF6 is known to function in cytokine signaling during inflammatory responses. However, not much is known about its role in myogenic differentiation and muscle regeneration. We showed here that TRAF6 and its intrinsic ubiquitin E3 ligase activity are required for myogenic differentiation. In mouse myoblasts, knockdown of TRAF6 compromised the p38 MAPK and Akt pathways, while deliberate activation of either pathway rescued the differentiation defect caused by TRAF6 knockdown. TAK1 acted as a key signal transducer downstream of TRAF6 in myogenic differentiation. In vivo, knockdown of TRAF6 in mouse muscles compromised the injury-induced muscle regeneration without impairing macrophage infiltration and myoblast proliferation. Collectively, we demonstrated that TRAF6 promotes myogenic differentiation and muscle regeneration via the TAK1/p38 MAPK and Akt pathways.
p38 丝裂原活化蛋白激酶（MAPK）是一种参与肌发生分化的必需激酶。尽管已经鉴定出许多 p38 MAPK 的底物，但在肌发生分化过程中，其上游激活剂知之甚少。TRAF6 已知在炎症反应中的细胞因子信号转导中发挥作用。然而，关于其在肌发生分化和肌肉再生中的作用知之甚少。我们在这里表明，TRAF6 及其内在的泛素 E3 连接酶活性对于肌发生分化是必需的。在小鼠成肌细胞中，TRAF6 的敲低会损害 p38 MAPK 和 Akt 通路，而故意激活这两条通路则可以挽救 TRAF6 敲低引起的分化缺陷。TAK1 作为 TRAF6 在肌发生分化中的关键信号转导子。在体内，在小鼠肌肉中敲低 TRAF6 会损害损伤诱导的肌肉再生，而不会损害巨噬细胞浸润和成肌细胞增殖。总的来说，我们证明 TRAF6 通过 TAK1/p38 MAPK 和 Akt 通路促进肌发生分化和肌肉再生。
