Dystrophin Involved in the Susceptibility of Slow Muscles to Hindlimb Unloading via Concomitant Activation of TGF-β1/Smad3 Signaling and Ubiquitin–Proteasome Degradation in Mice
Dystrophin Involved in the Susceptibility of Slow Muscles to Hindlimb Unloading via Concomitant Activation of TGF-β1/Smad3 Signaling and Ubiquitin–Proteasome Degradation in Mice
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DOI：
10.1007/s12013-014-0023-4
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发表时间：
2014-05
影响因子：
2.6
通讯作者：
Peng Zhang;Wenjiong Li;Hongju Liu;Jinglong Li;Jing Wang;Yanan Li;Xiaoping Chen;Zhong-Hua Yang;Ming Fan
中科院分区：
文献类型：
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作者：
Peng Zhang;Wenjiong Li;Hongju Liu;Jinglong Li;Jing Wang;Yanan Li;Xiaoping Chen;Zhong-Hua Yang;Ming Fan
虽然众所周知，缓慢抽动的肌肉容易受到微重力条件的影响，但这种现象背后的分子和细胞机制仍不清楚。肌营养不良蛋白是连接细胞骨架和细胞外基质的重要纽带，被认为与骨骼肌力的产生和机械稳定有关。我们的研究表明，在C57BL/10小鼠后肢去负荷14天后，肌营养不良蛋白在快抽动肌纤维中的表达显著下调，而在慢抽动肌纤维中的表达上调。为了研究dystrophin在Hu诱导的肌肉萎缩易感性中的作用，我们比较了dystrophin缺陷(MDX)和野生型(WT)小鼠慢抽动比目鱼肌的降解信号机制。我们发现，与对照组相比，mdx组小鼠的肌肉质量和肌纤维横截面积减少得更少。此外，在泛素-蛋白酶体介导的肌肉降解中起关键作用的两种泛素连接酶(MuRF1，Atrogin-1)在后肢去负荷的MDX小鼠比目鱼肌中的表达显著下调。相比之下，在未负荷的WT小鼠比目鱼肌中，这些连接酶显著上调。后肢去负荷组mdx小鼠转化生长因子β(转化生长因子β1)/Smad3的表达降低，而WT小鼠后肢去负荷组该生长因子的表达增强。相应地，由于mdx小鼠的HU，肌球蛋白重链和肌钙蛋白I的四种亚型的表达减少，或者表现出延迟的从慢到快的转变。综上所述，我们的结果表明，dystrophin在慢抽动肌肉的废用性萎缩中发挥了中介和积极的作用。这种作用是通过激活转化生长因子-Smad1/β信号通路和下游泛素-蛋白酶体途径来实现的。
While it is well known that the slow-twitch muscles are vulnerable to microgravity conditions, the molecular and cellular mechanisms underlying this phenomenon remain unknown. Dystrophin, which constitutes an important link between the cytoskeleton and the extracellular matrix, is hypothesized to be involved in force generation and mechanical stabilization of the skeletal muscle. Here we have shown that after a 14-day hindlimb unloading (HU) of the C57BL/10 mice, the expression of dystrophin was significantly down-regulated in the fast-twitch myofibers, while in the slow-twitch myofibers, it was up-regulated. In order to investigate the role of dystrophin in HU-induced susceptibility to muscle atrophy, we compared the degradation signaling mechanisms of slow-twitch soleus muscle in dystrophin-deficient (mdx) and the wild-type (WT) mice. We found that mdx mice manifest less reduction of muscle mass and myofiber cross-sectional area than the control animals. Also, the expression of two ubiquitin ligases (MuRF1, Atrogin-1), which plays a crucial role in the ubiquitin–proteasome-mediated muscular degradation, was significantly down-regulated in soleus muscle of the hindlimb-unloaded mdx mice. In comparison, in the soleus muscle of unloaded WT mice, these ligases were significantly up-regulated. Whereas the hindlimb unloading reduced the expression of transforming growth factor β (TGF-β1)/Smad3 in mdx mice, in WT mice, the expression of this growth factor was augmented in response to unloading. Correspondingly, as a result of HU of the mdx mice, the expression of four subtypes of the myosin heavy chain and troponin I was reduced or it exhibited a delayed slow-to-fast transition. In summary, our results suggest that dystrophin exerts an intermediary and positive role in the disuse atrophy of the slow-twitch muscles. This effect is mediated through the activation of TGF-β1/Smad3 signaling and downstream ubiquitin–proteasome pathway.