Histone deacetylase 4 and neural activity-dependent muscle remodeling and atrophy

组蛋白脱乙酰酶 4 和神经活动依赖性肌肉重塑和萎缩

基本信息

批准号：
8303016
负责人：
TSO-PANG YAO
金额：
$ 32.62万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303016
关键词：
Aging Applications Grants Atrophic Binding Calcium Calmodulin Cell Nucleus Cells Clinical Treatment Complex Denervation Development Diabetes Mellitus Disease Dissociation Event Fiber Functional disorder Gene Expression Gene Mutation Gene Transfer Genetic Transcription Goals HDAC4 gene Health Histone Deacetylase Histone Deacetylase Inhibitor Insulin Resistance Lead Link Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Molecular Motor Neurons Muscle Muscle Development Muscle Fibers Muscle function Muscular Atrophy Myopathy Neuromuscular Diseases Neuromuscular Junction Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Export Operative Surgical Procedures Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiological Processes Process Property Protein Dephosphorylation Protein phosphatase Proteins Recruitment Activity Regulation Role Signal Pathway Signal Transduction Skeletal Muscle Transcription Repressor/Corepressor Translating base calmodulin-dependent protein kinase II effective therapy human HDAC4 protein insight meetings neuromuscular neuromuscular activity neuroregulation novel novel therapeutics programs relating to nervous system response trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): The dynamic remodeling of skeletal muscle in size and fiber type composition is a critical adaptive response to meet different functional demands. However, this neural activity-dependent process also contributes to devastating disease states, such as muscle atrophy associated with neuromuscular dysfunction. Elucidating the molecular pathway that connects neural activity to muscle remodeling machinery would not only provide insight into this dynamically regulated physiological process but also offer opportunities for the development of effective therapy for muscle disease such as atrophy. Toward this goal, we have identified HDAC4, a negative regulator of MEF2 transcription factors, as a potential protein critical for neuromuscular activity-dependent muscle atrophy and remodeling. We found that HDAC4 is dramatically and invariably induced and activated in response to denervation and neuromuscular disease-induced atrophy. We have also found that HDAC4 is dynamically associated with the neuromuscular junction (NMJ) where it co-localizes with calcium/calmodulin dependent kinases (CaMK) and 14-3-3, two signaling effectors of neuromuscular activity that were previously shown to regulate HDAC4 function and subcellular localization. Interestingly, upon denervation, HDAC4 dissociates from the NMJ and becomes concentrated to the nucleus in muscle fibers. We showed that HDAC4 can repress the expression of contractile, structural and metabolic proteins implicated in muscle atrophy and remodeling. We propose that HDAC4 is a critical mediator that controls neuromuscular activity-dependent transcriptional reprogramming associated with muscle atrophy and fiber type specification. Aim 1. To characterize the mechanism by which neural activity regulates HDAC4 expression and activity. We will elucidate the mechanism by which HDAC4 is induced transcriptionally and characterize the regulation of CaMK-dependent HDAC4 phosphorylation and intracellular trafficking in response to neuromuscular dysfunction. Aim 2. To elucidate the function of HDAC4 in muscle remodeling, atrophy and fiber type transition in response to neuromuscular inactivity. We propose to use genetic mutation, gene transfer and pharmacological HDAC inhibitor to characterize the role of HDAC4 in the execution of muscle atrophy and fiber type transition in response to reduced neuromuscular activity. The proposed study will provide a critical and novel understanding of the signaling events that link neuromuscular activity to muscle remodeling as well as pathological atrophy and metabolic disorders. Given that HDAC4 activity can be inhibited pharmacologically, the proposed study could potentially be translated into a novel clinical treatment for muscle atrophy or muscle disorders associated with neuromuscular dysfunction. PUBLIC HEALTH RELEVANCE: Muscle function and property are controlled by neural input. Neural inactivity caused by neuromuscular disease and aging can lead to muscle atrophy and myofiber transition that contributes to insulin resistance. Elucidating the machinery and signaling pathway that connects neural activity to the reprogramming of muscle phenotype would therefore provide novel therapeutic opportunities for treating muscle atrophy and type II diabetes.

描述（由申请人提供）：骨骼肌尺寸和纤维类型组成的动态重塑是满足不同功能需求的关键适应性反应。然而，这种依赖于神经活动的过程也会导致破坏性的疾病状态，例如与神经肌肉功能障碍相关的肌肉萎缩。阐明连接神经活动与肌肉重塑机制的分子途径不仅可以深入了解这种动态调节的生理过程，还可以为开发肌肉疾病（例如萎缩）的有效疗法提供机会。为了实现这一目标，我们确定了 MEF2 转录因子的负调节因子 HDAC4 作为一种对神经肌肉活动依赖性肌肉萎缩和重塑至关重要的潜在蛋白质。我们发现，HDAC4 因去神经支配和神经肌肉疾病引起的萎缩而被显着且总是被诱导和激活。我们还发现 HDAC4 与神经肌肉接头 (NMJ) 动态相关，在神经肌肉接头 (NMJ) 中，HDAC4 与钙/钙调蛋白依赖性激酶 (CaMK) 和 14-3-3 共定位，这两种神经肌肉活动的信号传导效应器先前已被证明可以调节 HDAC4功能和亚细胞定位。有趣的是，去神经支配后，HDAC4 从 NMJ 解离并集中到肌纤维的细胞核。我们发现 HDAC4 可以抑制与肌肉萎缩和重塑有关的收缩蛋白、结构蛋白和代谢蛋白的表达。我们认为 HDAC4 是控制与肌肉萎缩和纤维类型规范相关的神经肌肉活动依赖性转录重编程的关键介质。目标 1. 表征神经活动调节 HDAC4 表达和活性的机制。我们将阐明 HDAC4 转录诱导的机制，并表征 CaMK 依赖性 HDAC4 磷酸化和细胞内运输对神经肌肉功能障碍的调节。目标 2. 阐明 HDAC4 在响应神经肌肉不活动的肌肉重塑、萎缩和纤维类型转变中的功能。我们建议使用基因突变、基因转移和药理学 HDAC 抑制剂来表征 HDAC4 在执行肌肉萎缩和纤维类型转变（响应神经肌肉活动减少）中的作用。拟议的研究将为将神经肌肉活动与肌肉重塑以及病理性萎缩和代谢紊乱联系起来的信号事件提供批判性和新颖的理解。鉴于 HDAC4 活性可以在药理学上受到抑制，拟议的研究有可能转化为一种新的临床治疗方法，用于治疗肌肉萎缩或与神经肌肉功能障碍相关的肌肉疾病。公共健康相关性：肌肉功能和特性由神经输入控制。神经肌肉疾病和衰老引起的神经不活动可导致肌肉萎缩和肌纤维转变，从而导致胰岛素抵抗。因此，阐明连接神经活动与肌肉表型重编程的机制和信号通路将为治疗肌肉萎缩和 II 型糖尿病提供新的治疗机会。