ASICs as metabolic sensors in muscle afferents

描述（由申请人提供）： 在最大运动或缺血时，血液供应不足以满足骨骼肌的代谢需求，因此代谢副产物产生并积累。支配肌肉的感觉神经（传入神经）对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，但感受这些化学物质的受体的分子身份还没有得到很好的理解。酸敏感离子通道（ASIC）适合于感知肌肉中的细胞外化学变化。我们的总体目标是了解在肌肉缺血和运动的相关条件下，ASICs作为受体在肌肉传入中的作用。我们的建议的一个优势是，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知疼痛和运动的理解，并为未来的研究和潜在的治疗提供目标。具体而言，我们的目标是：1）确定骨骼肌传入中ASIC通道的亚基组成; 2）确定ASIC受其他代谢物调节的机制; 3）确定ASIC代谢受体在缺血和运动中的作用。这些研究将为疼痛性疾病（如外周血管疾病引起的跛行、镰状细胞病相关疼痛、纤维肌痛、肌肉损伤和其他疼痛性肌肉疾病）的分子机制提供重要见解。此外，我们的研究结果将为肌肉传入感觉肌肉代谢变化和激活运动介导的反射的机制提供分子见解。此外，我们的研究对常见的心血管疾病有影响。心力衰竭现在是美国住院治疗的最常见原因。众所周知，交感神经系统的增加在疾病的进展中起着重要作用，我们的许多药物治疗旨在阻断这种交感神经兴奋。肌肉传入活动是导致这种高交感神经紧张的主要机制之一，并且肌肉反射的改变被认为是导致心力衰竭患者运动耐受性差的原因。越来越多的证据表明ASIC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.