ASICs as metabolic sensors in muscle afferents

描述(由申请人提供)： 项目摘要/摘要在极量运动或缺血期间，血液供应不足以满足骨骼肌的代谢需求，因此代谢副产物会产生和积累。支配肌肉的感觉神经(传入)对新陈代谢环境中的这些变化做出反应，并集中发送信号。这些信号可以启动运动介导的反射，有时它们还发出肌肉疼痛的信号。多种化学物质已被证明可以激活肌肉传入，但感知这些化学物质的受体的分子特性还不是很清楚。酸敏离子通道(ASIC)适合于感知肌肉细胞外的化学变化。我们的总体目标是了解ASICs作为受体在肌肉缺血和运动相关条件下的肌肉传入中的作用。我们的提议的一个优点是，我们已经开发出工具，在分子水平上解开肌肉传入激活的组成部分。这些研究将促进我们对肌肉传入如何感觉疼痛和运动的理解，并为未来的研究和潜在的治疗提供一个靶点。具体地说，我们的目标是：1)确定骨骼肌传入中ASIC通道的亚单位组成；2)确定ASIC受其他代谢物调节的机制；以及3)确定ASIC代谢物受体在缺血和运动中的作用。这些研究将为疼痛状况的分子机制提供重要的见解，如外周血管疾病导致的跛行、与镰状细胞疾病相关的疼痛、纤维肌痛、肌肉损伤和其他疼痛肌肉状况。此外，我们的结果将为肌肉传入如何感知肌肉新陈代谢变化和激活运动中介反射的机制提供分子洞察力。此外，我们的研究对常见的心血管疾病也有影响。心力衰竭现在是美国住院治疗最常见的原因。众所周知，交感神经系统的增加在疾病的发展中起着重要作用，我们的许多药物治疗都旨在阻止这种交感兴奋。肌肉传入活动是导致这种高交感神经张力的主要机制之一，肌肉反射的变化被认为是心力衰竭患者运动耐力差的原因之一。越来越多的证据表明ASICs是肌肉代谢环境的主要传感器，更好地了解它们的作用可以为治疗肌肉疼痛和心血管疾病提供分子靶点。

DESCRIPTION (provided by applicant): Project Summary/Abstract During maximal exercise or ischemia, blood supply is insufficient to meet the metabolic needs of skeletal muscle, and so metabolic by-products are produced and accumulate. Sensory nerves (afferents) that innervate muscle respond to these changes in the metabolic milieu, and send signals centrally. These signals can initiate exercise-mediated reflexes, and sometimes they signal muscle pain. Multiple chemicals have been shown to activate muscle afferents, but the molecular identity of the receptors that sense these chemicals are not well understood. Acid-Sensing Ion Channels (ASICs) are suited to sense extracellular chemical changes in muscle. Our overall goal is to understand the role of ASICs as receptors in muscle afferents during the related conditions of muscle ischemia and exercise. A strength of our proposal is that we have developed tools to unravel the components of muscle afferent activation at the molecular level. These studies will advance our understanding of how muscle afferents sense pain and exercise, and provide a target for future studies and potential therapies. Specifically, our Aims are to: 1) determine the subunit composition of ASIC channels in skeletal muscle afferents; 2) define the mechanisms by which ASICs are modulated by other metabolites; and 3) determine the role of ASICs metaboreceptors during ischemia and exercise. These studies will provide significant insight into the molecular mechanisms that underlie painful conditions such as claudication from peripheral vascular disease, pain associated with sickle cell disease, fibromyalgia, muscle injury, and other painful muscle conditions. Additionally, our results will provide molecular insight into the mechanisms how muscle afferents sense metabolic changes in muscle and activate exercise-mediated reflexes. Moreover, our studies have implications for common cardiovascular diseases. Heart failure is now the most common cause for hospitalization in the United States. It is well understood, that increases in the sympathetic nervous system plays a major role in the progression of the disease, and much of our pharmacological treatments are aimed at blocking this sympathoexcitation. Muscle afferent activity is one of the major mechanisms contributing to this high sympathetic tone, and alterations of muscle reflexes are believed to contribute to the poor exercise tolerance of patients with heart failure. Increasing evidence points to ASICs as a major sensor of the metabolic milieu of muscle, and better understanding of their role could provide a molecular target to treat muscle pain and cardiovascular diseases.