Mast Cell Role in Masseter Muscle Repair

描述(申请人提供)：约12%的美国人患有颞颌关节紊乱病(TMD)，主要是育龄妇女和TMD患者，超过60%的患者以咀嚼肌肉疼痛为主诉。肌肉疼痛已被证明与四肢肌肉向心性或离心性收缩后产生的炎症和肌肉纤维损伤有关，磨牙症期间向心性或离心性收缩后的颌肌也可能发生类似的疼痛。多项研究表明，咬肌的再生能力受损；然而，这种受损的细胞基础尚不清楚。有证据表明，咬肌损伤后卫星细胞的激活和增殖减少。然而，这种缺陷是否存在于卫星细胞的数量、它们对损伤中释放的因子的有效激活和增殖的能力还是在炎症反应机制中还有待确定。我们提供的初步证据表明，由于冻伤，咬肌的炎症反应可能会增强和延长，表现为肥大细胞数量的增加。肥大细胞已被证明不仅与损伤后肌肉活力的下降有关，而且可能与肌肉炎症相关的疼痛有关。因此，这项建议的目的之一是研究咬肌和肢体肌肉修复对冰冻损伤的反应，找出可能解释咬肌修复能力受损的差异，并检查肥大细胞反应如何可能有助于这种再生潜力的下降。标准化损伤模型复制自然发生的肌肉损伤 磨牙症期间的咀嚼肌对于我们理解导致TMD肌肉炎症和疼痛的过程至关重要。因此，我们还建议研究一个更具生理学相关性的肌肉损伤模型，以确定偏心和向心收缩引起的咬肌局部损伤是否也会产生增强的炎症反应，并导致延迟修复。提出了两个具体目标。具体目的1：研究冻伤后咬肌和胫骨前肌的炎症反应。这一特定目的旨在检验这样一种假设，即咬肌修复的主要缺陷存在于其对损伤的炎症反应中，表现为肥大细胞数量增加和反复坏死以及由此产生的纤维化修复；特定目标2：检查咬肌修复对向心性和偏心性收缩损伤的反应。为此，我们建议在实验刺激引起向心性或偏心性收缩后，检查咬肌肌纤维的损伤和修复。这个特定的目的将使我们能够通过实验测试这样的假设，即向心性或偏心性收缩，如在咬合或磨牙症期间经历的收缩，会导致咬肌中的肌肉纤维损伤，从而促使长期的炎症反应和修复延迟。

DESCRIPTION (provided by applicant): Temporomandibular disorders (TMD) affect approximately 12% of the US population, predominately women in their childbearing years and of those affected by TMD, greater than 60% have masticatory muscle pain as their main complaint. Muscle pain has been shown to be associated with inflammation and muscle fiber injury generated after concentric or eccentric contractions in limb muscle and may similarly occur in jaw muscle after concentric or eccentric contractions during bruxism. Several studies have demonstrated that the masseter muscle has an impaired regenerative capacity; however, the cellular basis for this impaired capacity is unknown. Evidence exists for decreased satellite cell activation and proliferation in masseter in response to injury. However, it has yet to be established if this defect resides in satellite cell number, in their ability to effectively activate and proliferate in response to factors released in injury or in inflammatory response mechanisms. We provide preliminary evidence that the inflammatory response may be augmented and prolonged in masseter in response to freeze-injury and is manifested by increased numbers of mast cells. Mast cells have been demonstrated to be not only associated with a decrease in muscle viability after damage, but also may be responsible for pain associated with muscle inflammation. Thus one objective of this proposal is to examine events in masseter and in limb muscle repair in response to a freeze injury, to detect differences that might explain the impaired repair capacity of the masseter and to examine how mast cell response may contribute to this decreased regenerative potential. Standardized injury models that duplicate naturally occurring muscle damage in masseter during bruxism are essential to our understanding of the processes that contribute to muscle inflammation and pain in TMD. Therefore, we propose to also examine a more physiologically relevant model of muscle injury to determine if localized damage to the masseter elicited by eccentric and concentric contractions also generates an augmented inflammatory response and results in delayed repair. Two specific aims are proposed. Specific Aim 1: Examine events in the inflammatory response to a freeze-induced injury in masseter and tibialis anterior. This specific aim is designed to test the hypothesis that the primary defect in masseter muscle repair resides in its inflammatory response to damage, manifested as increased numbers of mast cells and recurrent necrosis and resultant fibrotic repair; Specific Aim 2: Examine events in masseter muscle repair in response to damage from concentric and eccentric contraction. In this specific aim we propose to examine muscle fiber injury and repair in masseter after experimental stimulation to elicit concentric or eccentric contractions. This specific aim will allow us to experimentally test the hypothesis that concentric or eccentric contractions such as those experienced during jaw clenching or bruxism result in muscle fiber damage in the masseter that prompts a prolonged inflammatory response and delay in repair.