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

• 批准号: 7526562
• 负责人: TSO-PANG YAO
• 金额: $ 34.32万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7526562
• 关键词: Age; Aging; Applications Grants; Atrophic; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calmodulin; Cell Nucleus; Cells; Clinical Treatment; Complex; Condition; Denervation; Development; Diabetes Mellitus; Disease; Dissociation; Event; Fiber; Functional disorder; Gene Expression; Gene Mutation; Gene Transfer; Genetic Transcription; Goals; HDAC4 gene; Histone Deacetylase; Insulin Resistance; Lead; Link; Localized; 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; Public Health; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Transcription Repressor/Corepressor; Translating; base; calmodulin-dependent protein kinase II; human HDAC4 protein; inhibitor/antagonist; insight; neuromuscular activity; neuroregulation; novel; novel therapeutics; programs; relating to nervous system; response; size; trafficking; transcription factor

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）：骨骼肌大小和纤维类型组成的动态重塑是满足不同功能需求的关键自适应反应。然而，这种依赖神经活动的过程也有助于毁灭性疾病状态，例如与神经肌肉功能障碍相关的肌肉萎缩。阐明将神经活动与肌肉重塑机械联系起来的分子途径不仅可以洞悉这种动态调节的生理过程，而且还为开发有效的肌肉疾病疗法（如萎缩）提供了机会。为了实现这一目标，我们确定了HDAC4（MEF2转录因子的负调节剂）是对神经肌肉活性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是响应于神经肌肉疾病诱导的萎缩而急剧诱导和激活的。我们还发现，HDAC4与神经肌肉连接（NMJ）动态相关，在该神经肌肉连接（NMJ）与钙/钙调蛋白依赖蛋白激酶（CAMK）和14-3-3共定位，这是神经肌肉活性的两个信号传导效应子，这些信号传导因素先前被证明可调节HDAC4功能和细胞下局部定位。有趣的是，在神经支配后，HDAC4从NMJ中解离并集中在肌肉纤维中的细胞核上。我们表明，HDAC4可以抑制与肌肉萎缩和重塑有关的收缩，结构和代谢蛋白的表达。我们建议HDAC4是一个关键的介体，它控制着与肌肉萎缩和纤维类型规范相关的神经肌肉活性依赖性转录重编程。目的1。表征神经活动调节HDAC4表达和活性的机制。我们将阐明HDAC4在转录上诱导的机制，并表征CAMK依赖性HDAC4磷酸化和细胞内运输的调节，以响应神经肌肉功能障碍。目的2。阐明HDAC4在肌肉重塑，萎缩和纤维型转变中的功能，以响应神经肌肉不活跃。我们建议使用遗传突变，基因转移和药理学HDAC抑制剂来表征HDAC4在肌肉萎缩和纤维类型过渡中的作用，以响应降低神经肌肉活性。拟议的研究将对将神经肌肉活性与肌肉重塑以及病理萎缩和代谢性疾病联系起来的信号传导事件提供批判性的新了解。鉴于HDAC4活性可以在药理学上抑制，因此拟议的研究可能会被转化为与神经肌肉功能障碍相关的肌肉萎缩或肌肉疾病的新型临床治疗。公共卫生相关性：肌肉功能和财产由神经输入控制。神经肌肉疾病和衰老引起的神经不活跃会导致肌肉萎缩和肌纤维过渡，从而导致胰岛素抵抗。因此，阐明将神经活动与肌肉表型重编程联系起来的机械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。