Myonuclear homeostasis in craniofacial muscles

摘要/摘要 阿尔茨海默病(AD)是一种退行性大脑疾病，也是痴呆症最常见的形式。吞咽 吞咽困难是AD的早期症状，会导致严重咳嗽、营养不良和脱水 和/或吸入性肺炎，所有这些都降低了AD患者的生活质量，增加了AD的死亡率。 尽管尚不清楚AD早期肌肉萎缩和虚弱是如何发展的，但一个可检验的假说是有限的 由于吞咽困难而摄入的食物/水会导致肉质减少。在早期AD患者中，吞咽困难和骨骼减少 与AD的发病有关，但吞咽困难和体重减轻或 石棺减少症仍有待确定。吞咽困难的患者表现为咽肌萎缩和纤维化生， 它们是吞咽的关键肌肉。咽肌特异性病理，如吞咽困难，有 常见于几种神经肌肉疾病，尤其是迟发性集合体- 包括阿尔茨海默病在内的媒介疾病。一个主要的假说解释了许多蛋白质聚集体的迟发性-- 介导性疾病是指自噬功能随着年龄的增长而受损。我们在咽部发现了不同的自噬活动 老年小鼠肌肉与其他肌肉的比较，暗示自噬对维持咽部的作用 肌肉动态平衡。聚集体介导的疾病自噬功能受损可导致肌肉退化 以及随后由于失去肌纤维完整性而导致的纤维化和萎缩。纤维化是由纤维化引起的 营养不良患者巨噬细胞分化成纤维脂肪前体细胞及其细胞因子的研究 肌肉老化。这项提议的长期目标是了解细胞和分子通路 控制咽肌萎缩和纤维化，这可能为AD相关的治疗提供参考 吞咽困难。我们的实验室可以很好地研究咽部肌肉的病理，因为我们拥有 正常、衰老和营养不良条件下的咽肌间充质干细胞。我们建议两个 目的研究早期AD患者咽肌纤维化和吞咽困难的情况。在目标1中，我们将筛查吞咽困难 用舔舔法和咽部组织学方法观察AD模型小鼠的咽肌病理变化 肌肉。在目标2中，我们将研究AD咽肌中细胞因子的变化作为纤维化的机制 并使用巨噬细胞耗竭剂确定巨噬细胞在调节纤维化中的作用。通过完成 这些目标，我们希望揭示吞咽困难在AD早期的细胞机制。

Summary/Abstract Alzheimer’s disease (AD) is a degenerative brain disease and the most common form of dementia. Swallowing difficulty, called dysphagia, is an early symptom of AD, causing severe coughing, malnutrition, dehydration and/or aspiration pneumonia, all of which reduce the quality of AD patients’ lives and increase mortality of AD. Although it is unknown how muscle loss and weakness develop in early AD, a testable hypothesis is that limited food/water intake due to dysphagia leads to sarcopenia. In early AD patients, dysphagia and sarcopenia have been associated with onset of AD, yet the causative relationship between dysphagia and weight loss or sarcopenia remains to be determined. Dysphagia patients show atrophy with fibrosis of pharyngeal muscles, which are critical muscles for swallowing. Pharyngeal muscle specific pathology, such as dysphagia, has frequently been observed in several kinds of neuromuscular diseases, particularly late-onset aggregates- mediated diseases including AD. A leading hypothesis to explain of late-onset of many protein aggregates- mediated diseases is impaired autophagy with age. We found differential autophagy activity in pharyngeal muscles compared to other muscles in aged mice, implicating the role of autophagy to maintain pharyngeal muscle homeostasis. Impaired autophagy of aggregates-mediated diseases can lead to muscle degenerations and subsequent fibrosis and atrophy due to loss of myofiber integrity. Fibrosis is generated from fibrotic differentiation of fibroadipose progenitor cells by dysregulated macrophage and their cytokines in dystrophic or aged muscles. The long-term goal of this proposal is to understand the cellular and molecular pathways that control pharyngeal muscle atrophy and fibrosis, which can potentially inform the treatment for AD-related dysphagia. Our lab is well positioned to study pharyngeal muscle pathologies since we have expertise regarding mesenchymal stem cells of pharyngeal muscles in normal, aged and dystrophic conditions. We propose two aims to investigate pharyngeal muscle fibrosis and dysphagia in early AD. In aim 1, we will screen the dysphagia and pharyngeal muscle pathology of AD model mice using lick assay and histology analysis of pharyngeal muscles. In aim 2, we will investigate cytokine changes in AD pharyngeal muscles as a mechanism of fibrosis and determine the role of macrophages in regulating fibrosis using a macrophage depletion agent. By completing these aims, we expect to reveal cellular mechanisms of dysphagia in early AD.