Botulinum toxin in muscles of mastication

描述(申请人提供)：A型肉毒神经毒素(BONT/A)是一种有效的麻痹药，是一种广泛用于治疗咬肌的药物。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，但原因尚不清楚。可能的解释是运动单位的数量减少或卫星细胞种群的反应不佳，但到目前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。在临床使用中，咬合力比咬肌恢复得更快，但其机制尚不清楚。此外，声称用于BONT/A但未经证实的一个好处是，在肌肉瘫痪后，颌骨将被卸载。如果是这样，那么停用应该会导致骨质流失，但这也没有得到证实。这项拟议的研究是利用两个公认的人类咀嚼功能的动物模型--兔子和猪--系统地研究BONT/A对咬肌和下颌骨的影响。具体目标1将使用肌电图仪和运动分析来阐明肌肉使用的代偿模式是否会导致咬合力和咀嚼能力的提前恢复。具体目标2将通过应变片记录和骨结构的显微CT检查来评估注射侧下颌骨卸载的可能性。咬肌麻痹被认为是在非负荷区迅速出现骨量丢失。具体目标3将调查ONT/A麻痹是否会导致咬肌内运动单位的重组，并将采用神经追踪和神经刺激技术。对这种毒素的直接反应预计将是扩大通常高度受限的运动单位领土。运动神经元丢失的可能性也将被调查。具体目标4将建立肌肉退化和修复的过程，以探索为什么咬肌萎缩是长期存在的。卫星细胞群体的活动将通过复制和细胞死亡的标记以及通过跟踪肌球蛋白重链组成的变化来描述。总而言之，这个项目解决了常见临床治疗背后的生物学问题。它将提供有关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的神经可塑性程度的新信息。这些结果将为患者的治疗和解释结果提供一个知情的背景。与公共卫生相关：A型肉毒神经毒素，商业名称为肉毒杆菌毒素，可使肌肉瘫痪很长一段时间，在此期间肌肉萎缩，神经重组。数以千计的患者已经接受了这种药物，以缩小巨大的下颌肌肉。这项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。这些结果将指导临床医生理解功能后果，并有助于验证治疗的临床原理。

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.