Peter Angela K, Crosbie Rachelle H
Department of Physiological Science, University of California Los Angeles, CA 90095, USA.
Exp Cell Res. 2006 Aug 1;312(13):2580-91. doi: 10.1016/j.yexcr.2006.04.024. Epub 2006 May 22.
Dystrophic muscle undergoes repeated cycles of degeneration/regeneration, characterized by the presence of hypertrophic fibers. In order to elucidate the signaling pathways that govern these events, we investigated Akt activation in normal and dystrophic muscle. Akt is activated in neonatal muscle and in actively dividing myoblasts, supporting a developmental role for Akt signaling. Akt activation was detected at very early, prenecrotic stages of disease pathogenesis, and maximal activation was observed during peak stages of muscle hypertrophy. Duchenne muscular dystrophy patients exhibit a similar pattern of Akt activation. Mice with sarcoglycan-deficient muscular dystrophy possess more severe muscle pathology and display elevated Akt signaling. However, the highest levels of Akt activation were found in dystrophin-utrophin-deficient muscle with very advanced dystrophy. We propose that Akt may serve as an early biomarker of disease and that Akt activation mediates hypertrophy in muscular dystrophy. Current investigations are focused on introducing constitutively active and dominant-negative Akt into prenecrotic mdx mice to determine how early modification of Akt activity influences disease pathogenesis.
营养不良性肌肉经历反复的退化/再生循环，其特征是存在肥大纤维。为了阐明控制这些事件的信号通路，我们研究了正常和营养不良性肌肉中Akt的激活情况。Akt在新生肌肉和活跃分裂的成肌细胞中被激活，这支持了Akt信号传导在发育中的作用。在疾病发病机制的非常早期、坏死前阶段就检测到了Akt的激活，并且在肌肉肥大的高峰期观察到最大激活。杜氏肌营养不良症患者表现出类似的Akt激活模式。缺乏肌聚糖的肌肉营养不良小鼠具有更严重的肌肉病理变化，并表现出升高的Akt信号传导。然而，在具有非常晚期营养不良的抗肌萎缩蛋白- utrophin缺陷型肌肉中发现了最高水平的Akt激活。我们提出Akt可能作为疾病的早期生物标志物，并且Akt激活介导了肌肉营养不良中的肥大。目前的研究集中于将组成型激活和显性负性Akt引入坏死前的mdx小鼠中，以确定Akt活性的早期改变如何影响疾病发病机制。
