Systems analysis of transcriptional data provides insights into muscle's biological response to botulinum toxin-A (BoNT-A)

Introduction:The purpose of this study is to provide athe first global transcriptomic profiling and systems analysis of BoNT-A treated muscle over a one year period. Microarray analysis was performed on rat TA muscle from 4 groups (n=4/group) at 1,4, 12 and 52 weeks after BoNT-A injection and saline injected rats at 12 weeks as control. Fold changes were computed at each time point with respect to control. Results: Dramatic transcriptional adaptation occurs at 1 week with a paradoxical increase in expression of slow and immature isoforms; increased expression of genes in competing pathways of repair and atrophy; impaired mitochondrial biogenesis and increased metal ion imbalance. ECM adaptations occurred at 4weeks to the basal lamina and fibrillar ECM. The muscle transcriptome returned to the unperturbed state 12 weeks post-injection. Conclusion: Transcriptional adaptations resemble denervated muscle albeit some differences. Overall gene expression, across time, correlates with the generally accepted BoNT-A time course.引言：本研究旨在首次完成肉毒杆菌毒素A（BoNT-A）处理的肌肉在一年周期内的全局转录组谱分析与系统级分析。研究对4组大鼠胫骨前肌（Tibialis Anterior，TA）开展微阵列分析，每组样本量为4，采样时间分别为BoNT-A注射后1、4、12及52周；另设置12周时注射生理盐水的大鼠作为对照。以该对照组为参照，计算各时间点的基因表达倍数变化。 结果：注射后1周即出现显著的转录组适应性改变，表现为慢肌纤维与未成熟肌纤维亚型的表达反常升高；修复与萎缩竞争性通路的基因表达上调；线粒体生物发生受损，金属离子失衡加剧。注射后4周，细胞外基质（Extracellular Matrix，ECM）出现适应性改变，累及基膜与纤维状细胞外基质。注射后12周，肌肉转录组恢复至未受干扰的基线状态。 结论：尽管存在部分差异，该转录适应性变化与失神经支配肌肉的转录适应性相似。整体而言，随时间变化的基因表达模式与公认的BoNT-A作用时间进程相符。