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

描述（由申请人提供）：骨骼肌在大小和纤维类型组成上的动态重塑是满足不同功能需求的关键适应性反应。然而，这种依赖神经活动的过程也会导致毁灭性的疾病状态，例如与神经肌肉功能障碍相关的肌肉萎缩。阐明神经活动与肌肉重塑机制之间的分子通路，不仅可以深入了解这一动态调节的生理过程，还可以为开发有效治疗肌肉萎缩等疾病的方法提供机会。为了实现这一目标，我们已经确定了HDAC4， MEF2转录因子的负调节因子，作为神经肌肉活动依赖性肌肉萎缩和重塑的潜在关键蛋白。我们发现HDAC4在失神经支配和神经肌肉疾病引起的萎缩反应中被显著且不可避免地诱导和激活。我们还发现HDAC4与神经肌肉连接处（NMJ）动态相关，在那里它与钙/钙调蛋白依赖激酶（CaMK）和14-3-3共定位，这两种神经肌肉活动的信号效应物先前被证明可以调节HDAC4的功能和亚细胞定位。有趣的是，在去神经支配时，HDAC4从NMJ分离并集中到肌纤维中的核中。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。我们提出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。目的1。表征神经活动调控HDAC4表达和活性的机制。我们将阐明HDAC4通过转录诱导的机制，并表征camk依赖性HDAC4磷酸化和细胞内运输在神经肌肉功能障碍反应中的调节。目标2。阐明HDAC4在神经肌肉不活动时肌肉重塑、萎缩和纤维类型转换中的功能。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在神经肌肉活动减少时肌肉萎缩和纤维类型转变中的作用。该研究将为神经肌肉活动与肌肉重塑以及病理性萎缩和代谢紊乱之间的信号传导事件提供关键和新颖的理解。鉴于HDAC4活性可以被药理学抑制，该研究可能会转化为一种治疗肌肉萎缩或与神经肌肉功能障碍相关的肌肉疾病的新型临床治疗方法。公共卫生相关性：肌肉的功能和性质是由神经输入控制的。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移，从而导致胰岛素抵抗。因此，阐明神经活动与肌肉表型重编程之间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。

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.