Muscle Structure, Toxin Dose, and Exercise Affect Botulinum Toxin Efficiency

描述（由申请人提供）：A型肉毒杆菌毒素常用于通过诱导肌肉的“可逆化学去神经支配”来治疗神经肌肉骨骼损伤。尽管这种药物在康复医学中的应用越来越广泛，但对其对骨骼肌的短期和长期影响知之甚少。这些实验的目的是确定毒素引起的麻痹对肌肉结构、功能和修复的影响。为实现这一目标，提出了三个具体目标。第一个目的是确定BTX-A治疗对肌肉结构和功能的急性和慢性影响。我们的假设是BTX-A治疗导致侵略性，肌纤维变性和细胞外基质紊乱，导致主动和被动张力产生能力的丧失。第二个目的是了解指导最佳肉毒杆菌毒素递送的关键因素。我们的假设是，优化BTX-A的给药（剂量、体积和途径）需要了解结构复杂性、结缔组织基质、血管分布和与肌肉的神经肌肉连接分布。第三个目的是了解BTX-A在运动肌肉中改善功效的机制。我们假设治疗性运动增加了BTX-A的急性疗效，减少了急性全身副作用（通过均匀分布毒素和促进运动神经元摄取），并在需要重新给药时改善了慢性疗效。这些目标的含义可以从四个方面来衡量。首先，骨骼肌从反复注射中恢复的长期能力将被理解。其次，肉毒杆菌毒素给药的剂量指南将具有肌肉特异性，提高给药效果，减少副作用。第三，将对毒素传递反应中与功能相关的重要被动张力变化进行量化，并确定这些变化的机制。第四，提高BTX-A效率的机制，当输送增加运动将被理解。这项工作的临床意义在于了解药物干预与肌肉功能之间的相互作用。公共卫生相关性：A型肉毒毒素在康复医学中经常通过化学去神经肌肉来治疗身体损伤。这些实验旨在量化毒素-运动相互作用对骨骼肌的急性和慢性功能影响。

DESCRIPTION (provided by applicant): Botulinum toxin type A is frequently used to treat neuromusculoskeletal impairments by inducing "reversible chemical denervation" of a muscle. Despite the widespread and increasing utilization of this drug in rehabilitation medicine, little is known about its short and long terms effects on skeletal muscle. The purpose of these experiments is to determine the effects of toxin -induced paralysis on muscle structure, function, and repair. To achieve this goal, three specific aims are proposed. The first aim is to determine the acute and chronic effects of BTX-A treatment on muscle structure and function. Our hypothesis is that BTX-A treatment causes aggressive, muscle fiber degeneration and deranged extracellular matrix resulting in loss of active and passive tension-generating capacity. The second aim is to understand the critical factors guiding on optimal botulinum toxin delivery. Our hypothesis is that optimizing BTX-A delivery (dose, volume, and route) requires an understanding of the architectural complexity, connective tissue matrix, vascularity, and neuromuscular junction distribution with the muscle. The third aim is to understand the mechanism of improved BTX-A efficacy in exercised muscles. We hypothesize therapeutic exercise increases the acute efficacy of BTX-A, reduces acute systemic side effects (by uniformly distributing the toxin and promoting motor neuron uptake), and improves chronic efficacy when redosing is required. The implications of these aims can be measured in four ways. First, the long term ability of skeletal muscle to recover from repeated injections will be understood. Second, the dosing guidelines for botulinum toxin delivery will become muscle specific, improving the efficacy of drug delivery and reducing side-effects. Third, the functionally important passive-tension related changes in response to toxin delivery will be quantified and the mechanism of these changes will be identified. Fourth, the mechanism of improved BTX-A efficiency when delivery is augmented with exercise will be understood. The clinical significance of this work lies in the understanding of the interaction between a pharmacological intervention and muscle function. PUBLIC HEALTH RELEVANCE: Botulinum toxin type A is frequently used to treat physical impairments in rehabilitation medicine by chemically denervating muscle. These experiments aim to quantify the acute and chronic functional effects of toxin - exercise interactions on skeletal muscle.