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

描述(申请人提供)：骨骼肌在大小和纤维类型组成上的动态重构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，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途径，不仅可以深入了解这一动态调节的生理过程，而且为开发肌肉萎缩等疾病的有效治疗方法提供了机会。为了实现这一目标，我们已经确定MEF2转录因子的负调控因子HDAC4是一种潜在的蛋白质，对神经肌肉活动依赖型肌肉萎缩和重塑至关重要。我们发现，HDAC4在去神经和神经肌肉疾病诱导的萎缩中被戏剧性地和始终如一地诱导和激活。我们还发现，HDAC4与神经肌肉接头(NMJ)是动态相关的，在那里它与钙/钙调蛋白依赖性蛋白激酶(CaMK)和14-3-3共存，这两个神经肌肉活动的信号效应器先前被证明调节HDAC4的功能和亚细胞定位。有趣的是，在去神经支配时，HDAC4从NMJ解离，并集中在肌肉纤维的核中。我们发现HDAC4可以抑制与肌肉萎缩和重塑有关的收缩、结构和代谢蛋白的表达。我们认为，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动依赖的转录重编程。目的1.研究神经活动调节HDAC4表达和活性的机制。我们将阐明HDAC4被转录诱导的机制，并表征在神经肌肉功能障碍时依赖于CaMK的HDAC4磷酸化和细胞内转运的调节。目的2.阐明HDAC4在肌肉重构、萎缩和神经肌无力所致的纤维类型转变中的作用。我们建议使用基因突变、基因转移和药物HDAC抑制剂来表征HDAC4在肌肉萎缩和纤维类型转变中的作用，以响应神经肌肉活动的减少。这项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一个关键和新颖的理解。鉴于HDAC4活性可以被药物抑制，这项拟议的研究可能被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临床疗法。与公共健康相关：肌肉功能和属性由神经输入控制。神经肌肉疾病和衰老引起的神经活动不足可能导致肌肉萎缩和肌纤维转变，从而导致胰岛素抵抗。因此，阐明将神经活动与肌肉表型重新编程联系起来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.