Preserving mitochondrial function for alleviating ALS progression

保护线粒体功能以缓解 ALS 进展

基本信息

批准号：
10155596
负责人：
Marco Brotto
金额：
$ 59.15万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155596
关键词：
ALS pathology ALS patients Address Affect Amyotrophic Lateral Sclerosis Autopsy Bacteria Biochemical Biology Biopsy Specimen Brain Butyrates Cell model Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Colon Communication Data Defect Denervation Dietary Fiber Dietary Supplementation Disease Progression Electrophysiology (science)Etiology Feedback Fermentation Functional disorder Genes Genetic Hand Strength Hormones Human Human Pathology Intervention Intestines Knowledge Leaky Gut Link Lipids Longevity Mediating Mediator of activation protein Metabolic Mitochondria Molecular Morphology Motor Neurons Mus Muscle Muscle Fibers Muscle Mitochondria Mutation Neuromuscular Diseases Neuromuscular Junction Neurons Organ Oxidative Stress Paralysed Pathogenesis Pathology Performance Physiological Physiology Play Predisposition Probiotics Production Property Quality of life Reactive Oxygen Species Reporting Research Role Series Signal Transduction Skeletal Muscle Spinal Cord Supplementation Symptoms Testing Therapeutic Transgenes Volatile Fatty Acids Withdrawal amyotrophic lateral sclerosis therapy dietary dysbiosis experimental study familial amyotrophic lateral sclerosis gastrointestinal gut bacteria gut homeostasis gut microbiome improved intestinal homeostasis lipidomics live cell imaging microbiome mitochondrial dysfunction mouse model muscle metabolism neuromuscular neuromuscular function neuromuscular system neuron loss novel novel therapeutic intervention preservation response restoration skeletal muscle wasting sporadic amyotrophic lateral sclerosis superoxide dismutase 1 tool

项目摘要

Project Summary Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease without cure. Most ALS are sporadic cases without identified genetic causes. However, the spinal cord and muscle autopsy/biopsy samples from both sporadic and familial ALS patients all show remarkable defects in morphology and biochemical properties of mitochondria. This indicates abnormal mitochondria as a common player in neuromuscular degeneration despite the etiology. Our research using the ALS mouse models (G93A), over the last 12 years, establishes a concept that mitochondrial dysfunction in skeletal muscle is part of the pathogenesis of ALS. Muscle appears to be a primary target of ALS mutation, in addition to being victim of neuronal withdrawal, because mitochondrial defects in muscle feedback to neuromuscular junction (NMJ) remodeling in ALS. Thus, restoration of mitochondrial function is a logical approach to alleviate the systemic symptom of ALS through fixing a common pathology. We made a novel discocery that ALS progression includes a leaky gut with an imbalanced microbiome (dysbiosis) in G93A mice. This gut defects occurs before the onset of ALS neuromuscular symptoms, suggesting that gut defects may play a role in ALS progression. We reported that the colon of G93A mice contained less butyrate-producing bacteria, and the dietary butyrate supplementation alleviated gut defects in G93A mice, improving their neuromuscular performance and extending their life span. Thus, our study brought a new concept that restoring gut homeostasis may provide an alternative means for improving neuromuscular function to treat ALS. Since the original submission, our collaboration with the Brotto Lab made several exciting new discoveries. We identified altered Lipidomics Profiles of ROS-related Bioactive Lipids (BLs) in muscle that were restored by one-month butyrate diet supplementation in G93A mice. Further, butyrate treatment directly enhanced muscle contractility. Our preliminary data also show that butyrate treatment improved mitochondrial function and its susceptibility to oxidative-stress induced damage in G93A muscle fibers. Our data suggest that butyrate could be an important mediator regulating the neuromuscular-gut integrative physiology. We hypothesize that integrative signaling between the neuromuscular system and gut contributes to the progressive loss of mitochondrial function in ALS, and restoration of butyrate- related microbiome has benefits in preserving mitochondrial function for treatment of ALS. The proposed study will address two fundamental questions: How do gut defects contribute to mitochondrial dysfunction of neuromuscular system in ALS (Aim 1)? Can neuromuscular-gut signaling be leveraged to improve mitochondrial function to slow ALS progression and/or improve the life quality of ALS patients (Aim 2)? While altered intestinal homeostasis and microbiome is linked to the human pathology of ALS, we anticipate that our study will bring novel concepts to the ALS research field. Knowledge gained from this study can have potential translational implications for developing new therapeutic strategies for combating ALS.

项目概要肌萎缩侧索硬化症（ALS）是一种致命的神经肌肉疾病，无法治愈。大多数 ALS 是散发性的未确定遗传原因的病例。然而，脊髓和肌肉尸检/活检样本来自散发性和家族性 ALS 患者均表现出明显的形态和生化特性缺陷线粒体。这表明异常线粒体是神经肌肉变性的常见参与者尽管有病因。我们在过去 12 年中使用 ALS 小鼠模型 (G93A) 进行的研究建立了骨骼肌线粒体功能障碍是 ALS 发病机制的一部分。肌肉出现除了成为神经元退缩的受害者之外，还成为 ALS 突变的主要目标，因为 ALS 中神经肌肉接头 (NMJ) 重塑的肌肉反馈中的线粒体缺陷。因此，恢复线粒体功能是缓解 ALS 全身症状的合理方法修复常见的病理学。我们做出了一项新颖的发现，即 ALS 进展包括肠漏 G93A 小鼠的微生物组失衡（生态失调）。这种肠道缺陷发生在 ALS 发病之前神经肌肉症状，表明肠道缺陷可能在 ALS 进展中发挥作用。我们报道称 G93A小鼠的结肠中产生丁酸盐的细菌较少，并且饮食中补充丁酸盐减轻了 G93A 小鼠的肠道缺陷，改善了它们的神经肌肉性能并延长了它们的寿命。因此，我们的研究提出了一个新概念，即恢复肠道稳态可能提供另一种方法改善神经肌肉功能以治疗 ALS。自最初提交以来，我们与 Brotto 的合作实验室取得了一些令人兴奋的新发现。我们发现 ROS 相关生物活性的脂质组学谱发生了改变 G93A 小鼠通过补充一个月的丁酸盐饮食可恢复肌肉中的脂质 (BL)。更远，丁酸盐治疗直接增强肌肉收缩力。我们的初步数据还表明丁酸盐治疗改善了 G93A 线粒体功能及其对氧化应激诱导损伤的易感性肌肉纤维。我们的数据表明丁酸盐可能是调节神经肌肉肠道的重要介质综合生理学。我们假设神经肌肉系统和神经肌肉系统之间的整合信号传导肠道导致 ALS 中线粒体功能的逐渐丧失，以及丁酸的恢复相关微生物组有利于保留线粒体功能以治疗 ALS。这拟议的研究将解决两个基本问题：肠道缺陷如何导致线粒体 ALS 中神经肌肉系统功能障碍（目标 1）？可以利用神经肌肉-肠道信号传导来改善线粒体功能以减缓 ALS 进展和/或改善 ALS 患者的生活质量（目标 2）？虽然肠道稳态和微生物组的改变与 ALS 的人类病理学有关，但我们预计我们的研究将为 ALS 研究领域带来新的概念。从这项研究中获得的知识对于开发抗 ALS 的新治疗策略具有潜在的转化意义。