Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Cell Biochem. 2011 Aug;112(8):2149-59. doi: 10.1002/jcb.23136.
Muscle inactivity due to injury or disease results in muscle atrophy. The molecular mechanisms contributing to muscle atrophy are poorly understood. However, it is clear that expression of atrophy-related genes, like Atrogin-1 and MuRF-1, are intimately tied to loss of muscle mass. When these atrophy-related genes are knocked out, inactive muscles retain mass. Muscle denervation stimulates muscle atrophy and Myogenin (Myog) is a muscle-specific transcription factor that is highly induced following muscle denervation. To investigate if Myog contributes to muscle atrophy, we have taken advantage of conditional Myog null mice. We show that in the denervated soleus muscle Myog expression contributes to reduced muscle force, mass, and cross-sectional area. We found that Myog mediates these effects, at least in part, by regulating expression of the Atrogin-1 and MuRF-1 genes. Indeed Myog over-expression in innervated muscle stimulates Atrogin-1 gene expression and Myog over-expression stimulates Atrogin-1 promoter activity. Thus, Myog and the signaling cascades regulating its induction following muscle denervation may represent novel targets for therapies aimed at reducing denervation-induced muscle atrophy.
由于损伤或疾病导致的肌肉活动不足会导致肌肉萎缩。导致肌肉萎缩的分子机制尚不清楚。然而，很明显，与肌肉萎缩相关的基因（如 Atrogin-1 和 MuRF-1）的表达与肌肉质量的丧失密切相关。当这些与萎缩相关的基因被敲除时，不活跃的肌肉会保留质量。肌肉失神经支配会刺激肌肉萎缩，而肌细胞生成素（Myogenin，Myog）是一种肌肉特异性转录因子，在肌肉失神经支配后会被高度诱导。为了研究 Myog 是否有助于肌肉萎缩，我们利用了条件性 Myog 缺失小鼠。我们发现，在失神经支配的比目鱼肌中，Myog 的表达有助于减少肌肉力量、质量和横截面积。我们发现，Myog 通过调节 Atrogin-1 和 MuRF-1 基因的表达来介导这些效应，至少在一定程度上是这样。事实上，Myog 在神经支配的肌肉中的过表达会刺激 Atrogin-1 基因的表达，而 Myog 的过表达会刺激 Atrogin-1 启动子的活性。因此，Myog 及其在肌肉失神经支配后调节其诱导的信号级联可能代表了旨在减少失神经支配引起的肌肉萎缩的新型治疗靶点。
