Botulinum toxin in muscles of mastication

描述（由申请人提供）：A型肉毒杆菌神经毒素（BoNT/A）是一种强效麻痹剂，广泛用于咬肌治疗。临床报告表明BoNT/A治疗的一些效果（萎缩，电活动减少）在颌骨肌肉中异常持久，但其原因尚不清楚。可能的解释是运动单元数量的减少或卫星细胞群的不良反应，但迄今为止还没有进行动物研究来研究毒素治疗后颌骨肌肉的生物学。在临床应用中，咬合力比咬肌恢复得更快，但其机制尚不清楚。此外，BoNT/A的一个好处是肌肉麻痹后下颌会被卸下，但尚未得到证实。如果是这样，那么就会导致骨质流失，但这一点也没有得到证实。本研究采用兔和猪两种公认的人类咀嚼功能动物模型，对BoNT/ a对咬肌和下颌骨的影响进行了系统的研究。具体目标1将使用肌电图和运动分析来阐明肌肉使用的代偿模式是否解释了咬合力和咀嚼能力的早期恢复。具体目标2将通过应变计记录和骨结构的显微ct检查来评估注射侧下颌骨的可能卸载。咬肌麻痹被认为是随后在卸载区域迅速丢失骨量。具体目标3将研究BoNT/A麻痹是否会导致咬肌内运动单元的重组，并将采用神经追踪和神经刺激技术。对毒素的直接反应是通常高度受限的运动单元领土的扩张。运动神经元丢失的可能性也将被研究。具体目标4将建立肌肉退化和修复的过程，以探讨为什么咬肌萎缩是持久的。卫星细胞群的活性将通过复制和细胞死亡标记物以及肌球蛋白重链组成的变化来描述。总而言之，该项目涉及一种常见临床治疗的生物学基础。它将提供关于肌肉及其神经如何受到影响，颌骨生物力学如何改变以及颌骨运动系统神经可塑性程度的新信息。结果将为患者治疗和解释结果提供知情背景。公共卫生相关性：A型肉毒杆菌神经毒素，更广为人知的商业名称是肉毒杆菌毒素，使肌肉长时间瘫痪，在此期间肌肉萎缩，神经重组。成千上万的病人已经服用了这种药物来收缩大块的下颌肌肉。拟议的研究将使用动物模型来研究咀嚼系统如何适应毒素和再生反应的生物学。结果将指导临床医生了解功能后果，并有助于验证治疗的临床依据。

DESCRIPTION (provided by applicant): Botulinum neurotoxin type A (BoNT/A), a potent paralytic, is a widely used treatment for the masseter muscles. Clinical reports suggest that some effects of BoNT/A treatment (atrophy, reduced electrical activity) are unusually long-lasting in jaw muscles, but the reasons for this are not clear. Possible explanations are reduction in the number of motor units or a poor response of the satellite cell population, but as yet no animal studies have been performed to study the biology of jaw muscles after toxin treatment. In clinical usage, bite force recovers more rapidly than the masseter, but the mechanism for this is unknown. Additionally, one benefit claimed for BoNT/A but unproven is that the jaw will be unloaded after muscle paralysis. If so, then disuse loss of bone should result, but this too is undemonstrated. The proposed research is a systematic examination of the effects of BoNT/A on the masseter muscle and the mandible, using two accepted animal models of human masticatory function, rabbit and pig. Specific Aim 1 will use electromyography and motion analysis to clarify whether compensatory patterns of muscle usage account for the early return of bite force and masticatory ability. Specific Aim 2 will assess the possible unloading of the injection side mandible by strain gage recording and microCT examination of bony architecture. Masseter paralysis is hypothesized to be followed rapidly by loss of bone mass in unloaded regions. Specific Aim 3 will investigate whether BoNT/A paralysis causes reorganization of motor units within the masseter and will employ neurotracing and nerve stimulation techniques. The immediate response to the toxin is expected to be expansion of normally highly restricted motor unit territories. The possibility of motor neuron loss will also be investigated. Specific Aim 4 will establish the course of muscle degeneration and repair to explore why atrophy is long-lasting in the masseter. The activity of the satellite cell population will be described through markers of replication and cell death and by tracking changes in myosin heavy chain composition. In summary, this project addresses the biology underlying a common clinical treatment. It will provide new information on how the muscles and their nerves are affected, how jaw biomechanics are altered, and the extent of neuroplasticity of the jaw motor system. The results will provide an informed background for patient treatment and for interpreting outcomes. PUBLIC HEALTH RELEVANCE: Botulinum neurotoxin type A, better known under the commercial name of Botox, paralyzes muscles for extended periods of time, during which the muscles atrophy and the nerves reorganize. Thousands of patients have received the drug in order to shrink large jaw muscles. The proposed research will use animal models to study how the chewing system adapts to the toxin and the biology of the regenerative response. The results will guide clinicians in understanding functional consequences and help to validate clinical rationales for treatment.