Ding Hui, Zhang Guohua, Sin Ka Wai Thomas, Liu Zhelong, Lin Ren-Kuo, Li Min, Li Yi-Ping
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.
Department of Respiratory Medicine, Yixing Hospital affiliated to Jiangsu University, Yixing, China.
J Cachexia Sarcopenia Muscle. 2017 Apr;8(2):202-212. doi: 10.1002/jcsm.12145. Epub 2016 Sep 16.
Activation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB-activated muscle catabolism is poorly defined.
We investigated the role of p38β mitogen-activated protein kinases (MAPK) in mediating ActRIIB ligand activin A-activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically.
Treatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK-independent mechanism. These events were followed by up-regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α-II), as well as increase in LC3-II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA-mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle-specific knockout of p38β MAPK. Interestingly, activin A up-regulated MuRF1 in a p38 MAPK-independent manner, and MuRF1 did not appear responsible for activin A-induced myosin heavy chain loss and muscle atrophy.
ActRIIB-mediated activation of muscle catabolism is dependent on p38β MAPK-activated signalling.
骨骼肌中IIB型激活素受体（ActRIIB）的激活会因肌肉蛋白质降解增加而导致肌肉萎缩。然而，介导ActRIIB激活的肌肉分解代谢的细胞内信号传导机制尚不清楚。
我们研究了p38β丝裂原活化蛋白激酶（MAPK）在介导ActRIIB配体激活素A激活的C2C12肌管以及通过药理学和遗传学方法干扰该激酶的小鼠肌肉分解代谢途径中的作用。
用激活素A或肌肉生长抑制素处理C2C12肌管在1小时内迅速激活p38 MAPK及其效应物C/EBPβ。矛盾的是，Akt同时通过一种不依赖p38 MAPK的机制被激活。这些事件之后是泛素连接酶atrogin1（MAFbx）和UBR2（E3α-II）的上调，以及自噬体形成标志物LC3-II的增加，导致肌原纤维蛋白丢失和肌管萎缩。p38α/β MAPK抑制剂SB202190消除了激活素A的分解代谢作用。使用小干扰RNA介导的基因敲低，我们发现激活素A的分解代谢活性特别依赖于p38β MAPK。重要的是，向小鼠全身注射激活素A同样在体内激活了分解代谢途径，并且这种作用被SB202190阻断。此外，激活素A在肌肉特异性敲除p38β MAPK的小鼠中未能激活分解代谢途径。有趣的是，激活素A以一种不依赖p38 MAPK的方式上调MuRF1，并且MuRF1似乎与激活素A诱导的肌球蛋白重链丢失和肌肉萎缩无关。
ActRIIB介导的肌肉分解代谢激活依赖于p38β MAPK激活的信号传导。
