Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Neurotrauma. 2010 Aug;27(8):1509-16. doi: 10.1089/neu.2010.1320.
Neurectomy and botulinum toxin A (BoNT-A) injection cause denervated muscle atrophy, but questions remain about their clinical utility. We investigated time-series alterations of rat muscle weight, functional deficits, signaling pathways, and microscopic structures, to gain an understanding of the clinical implications. Between 2008 and 2009, the maximal calf circumference of patients for calf reduction either by neurectomy or BoNT-A injections were recorded for study. A rat skeletal muscle model was established through repeated or dose-adjusted BoNT-A injections and neurectomy. The survival, apoptosis pathways, functional deficits, and microscopic structures were investigated using Western blot, sciatic functional index (SFI), and transmission electron microscopy (TEM), respectively. The rat muscle weight ratio of the BoNT-A group had recovered to 89.3 +/- 3.8% by week 58, but it never recovered in the neurectomy group. Muscle weight reduction by BoNT-A not only depended on the dose, but additive effects were also obtained through repeated injections. Rat SFI demonstrated rapid recovery in both groups. Molecular expressions showed a coherent and biphasic pattern. p-Akt and apoptosis-inducing factor (AIF) were upregulated significantly, with a peak at 8 weeks in the neurectomy group (p < 0.01), but cleaved caspase-9 and caspase-3 showed no significant changes in either group. TEM findings showed irreversible and reversible inner-structure disruption and sarcomere discontinuity in the neurectomy and BoNT-A groups, respectively. We demonstrated that denervation induced lasting muscle weight and structural changes of different degrees. Muscle weight reduction by BoNT-A was related to frequency and dose. AIF-mediated caspase-independent apoptosis was significantly different for neurectomy and BoNT-A injection.
神经切断术和肉毒毒素 A（BoNT-A）注射会导致去神经支配的肌肉萎缩，但它们的临床应用仍存在一些问题。我们研究了大鼠肌肉重量、功能缺陷、信号通路和微观结构的时间序列变化，以了解其临床意义。2008 年至 2009 年期间，我们记录了接受神经切断术或 BoNT-A 注射进行小腿缩小术的患者的小腿最大周长。通过重复或剂量调整的 BoNT-A 注射和神经切断术建立了大鼠骨骼肌模型。使用 Western blot、坐骨神经功能指数（SFI）和透射电子显微镜（TEM）分别研究了存活、凋亡途径、功能缺陷和微观结构。BoNT-A 组大鼠肌肉重量比在第 58 周恢复到 89.3 +/- 3.8%，但神经切断术组从未恢复。BoNT-A 引起的肌肉重量减少不仅取决于剂量，而且通过重复注射还可以获得累加效应。两组大鼠 SFI 均迅速恢复。分子表达呈一致的双相模式。神经切断术组 p-Akt 和凋亡诱导因子（AIF）显著上调，在第 8 周达到高峰（p < 0.01），但两组的裂解半胱天冬酶-9 和半胱天冬酶-3均无明显变化。TEM 发现神经切断术和 BoNT-A 组分别存在不可逆转和可逆的内部结构破坏和肌节不连续性。我们证明了去神经支配会引起不同程度的持续肌肉重量和结构变化。BoNT-A 引起的肌肉重量减少与频率和剂量有关。AIF 介导的 caspase 非依赖性凋亡在神经切断术和 BoNT-A 注射之间存在显著差异。
