Perm1 in skeletal muscle dysfunction induced by disuse and heart failure

Perm1 在废用和心力衰竭引起的骨骼肌功能障碍中的作用

• 批准号: 10454788
• 负责人: Robert Scott Ross
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454788
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Bed rest; Bioenergetics; Biogenesis; Ca(2+)-Calmodulin Dependent Protein Kinase; Chronic; Chronic Disease; Congestive Heart Failure; Data; Denervation; Dependovirus; Diabetes Mellitus; Disease; ERR1 protein; Exercise; Functional disorder; Future; Gene Expression; Gene-Modified; Genes; Hand; Health; Heart; Heart Diseases; Heart failure; Immobilization; Injury; Knock-out; Lead; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morphology; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Proteins; Muscle function; Muscular Atrophy; Organism; PPAR gamma; Pathologic; Pathology; Patients; Phosphotransferases; Physical Exercise; Physical activity; Population; Protein Kinase; Publishing; Recovery; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Striated Muscles; Testing; Transcription Coactivator; Veterans; Virus; Work; base; calmodulin-dependent protein kinase II; clinical application; constriction; estrogen-related receptor; exercise capacity; exercise intolerance; functional adaptation; gene therapy; improved; in vivo; man; mouse model; muscle form; muscle metabolism; novel; novel strategies; prevent; programs; skeletal muscle wasting; skeletal muscle weakness; therapeutic evaluation; transcription factor

Project Summary/Abstract Skeletal muscle (SkM) atrophy is a significant health problem associated with muscle disuse. It can frequently occur in association with diseases or treatments of any type that require bed rest or full immobilization. It can result nervous supply injury, or result from chronic diseases, such as cancer, AIDS, diabetes, and importantly, a focus of this proposal, chronic heart failure (HF). Increased physical activity and exercise reduce muscle atrophy or even accelerate its recovery, by causing SkM to undergo metabolic, contractile and morphological adaptations. These adaptations rely on signaling pathways that lead to changes in gene expression and enzymatic activity. Therefore, understanding the molecular mechanisms underlying muscle activity-induced signaling may provide novel basic information about muscle function and adaptation and ultimately could provide new approaches for treating muscle dysfunction, including muscle dysfunction in heart failure. We note that the transcriptional coactivator PGC-1 has been shown to be induced and activated by exercise, and regulate muscle metabolic programs. By using a microarray screen with a myotube model transduced with PGC-1 (PPARgamma coactivator 1) and ERR (Estrogen-related receptor) transcription factors, we identified a novel PGC-1 / ERR target gene, termed Perm1 (PGC-1 and ERR-induced regulator, muscle 1). Our published and preliminary data show that striated muscle protein (Perm1) impacts muscle bioenergetics, is induced by exercise, regulates expression of metabolic genes, and modifies muscle mitochondrial (Mito) biogenesis. Perm1 is also down-regulated in SkM with disuse and the presence of heart failure. Based on this strong preliminary data, we propose the central hypothesis that Perm1 integrates activity-induced signals and enhances muscle mitochondrial biogenesis and function. A corollary to this is that Perm1 acts by modulating activity/contraction–induced kinase signaling (CaMKII, calcium/calmodulin dependent protein kinase II). Through activity-induced signal integration, Perm1 may prevent disuse and HF - induced SkM dysfunction. To address this hypothesis, we have generated two novel mouse models in which Perm1 is either specifically increased in skeletal muscle (Perm1SkMTransgenic (TG)) or deleted from skeletal muscle (Perm1SkM knockout (KO)). This hypothesis will be pursued by the following specific aims: Aim 1. Study the role of Perm1 in metabolic and functional alterations induced by muscle disuse. We will use Perm1SkMTG and Perm1SkMKO mice to directly evaluate Perm1 function in basal and pathological states including denervation and cast immobilization. Aim 2. Study the role of Perm1 in Heart Failure-induced SkM dysfunction. We will study the role of Perm1 in HF-induced SkM dysfunction, comparing WT, to Perm1SkMTG, and Perm1SkMKO mice. We hypothesize Perm1SkMTG will be protected from HF-induced SkM weakness and exercise intolerance, while Perm1SkMKO mice will be susceptible to metabolic and functional deregulation induced by HF. Mechanism(s) by which Perm1 effects occur, such as CaMKII-related signaling will be pursued in this aim. Aim 3. Test the therapeutic benefits of Perm1 for treating SkM dysfunction induced by disuse and heart failure using a gene therapy approach. This aim will extend to translational work and test how alteration in Perm1 affects muscle function using an adeno-associated virus (AAV) -mediated gene therapy approach to test the therapeutic potential of Perm1 in ameliorating SkM dysfunction. We will test if augmentation of Perm1 expression in SkM will prevent or accelerate recovery from SkM dysfunction. The viruses and models are all in hand. This proposal should uncover important basic and translational information relevant to improve the health of Veterans with skeletal muscle dysfunction present from disuse and importantly, as a result of heart failure.

项目摘要/摘要 骨骼肌(SKM)萎缩是一个与肌肉停用相关的重大健康问题。它可以经常 与需要卧床休息或完全固定的任何类型的疾病或治疗有关。它可以 导致神经供应损伤，或由慢性病引起，如癌症、艾滋病、糖尿病，更重要的是， 这项建议的重点是慢性心力衰竭(HF)。增加体力活动和锻炼可减少肌肉萎缩 甚至通过使SKM经历新陈代谢、收缩和形态适应来加速其恢复。 这些适应依赖于导致基因表达和酶活性变化的信号通路。 因此，了解肌肉活动诱导信号传递的分子机制可能会提供 关于肌肉功能和适应的新的基本信息，最终可能提供新的方法 治疗肌肉功能障碍，包括心力衰竭的肌肉功能障碍。 我们注意到，转录共激活因子pGC-1已被证明在运动中被诱导和激活， 并调节肌肉代谢程序。通过使用带有肌管模型的微阵列屏幕 PGC-1(PPAR-γ共激活因子1)和ERR(雌激素相关受体)转录因子，我们鉴定了一种 新的PGC-1/ERR靶基因，命名为Perm1(PGC-1和ERR诱导的调节因子，肌肉1)。我们出版的 初步数据显示，横纹肌蛋白(Perm1)影响肌肉生物能量学，是由 运动，调节代谢基因的表达，并改变肌肉线粒体(MITO)的生物发生。Perm1 在停用和出现心力衰竭的情况下，SKM的表达也会下调。 基于这一强大的初步数据，我们提出了Perm1整合了活动诱导的中心假设 传递信号并增强肌肉线粒体的生物发生和功能。由此推论，Perm1的作用方式是 调节活性/收缩诱导的激酶信号(CaMKII，钙/钙调蛋白依赖的蛋白激酶 Ii)。通过活性诱导的信号整合，Perm1可能阻止废用和HF诱导的SKM功能障碍。 为了解决这一假设，我们产生了两个新的小鼠模型，其中Perm1是特定的 在骨骼肌中增加(Perm1SkM转基因(TG))或从骨骼肌中删除(Perm1SkM基因敲除 (KO))。这一假设将通过以下具体目标来实现： 目的1.研究Perm1在肌肉停用引起的代谢和功能改变中的作用。我们会 使用Perm1SkMTG和Perm1SkMKO小鼠直接评估Perm1在基础状态和病理状态下的功能 包括去神经和石膏固定。 目的2.研究Perm1在心力衰竭所致SKM功能障碍中的作用。我们将研究Perm1的作用 在HF诱导的SKM功能障碍中，将WT与Perm1SkMTG和Perm1SkMKO小鼠进行比较。我们假设 Perm1SkMTG将免受HF引起的SKM虚弱和运动不耐受的影响，而Perm1SkMKO 小鼠容易受到HF引起的代谢和功能失调的影响。机制(S)Perm1 效果发生了，例如CaMKII相关信号将在这一目标中进行。 目的3.测试Perm1治疗因停用和心脏引起的SKM功能障碍的疗效 使用基因治疗方法失败了。这一目标将延伸到翻译工作，并测试如何在 使用腺相关病毒(AAV)介导的基因治疗方法测试Perm1影响肌肉功能 Perm1改善SKM功能障碍的治疗潜力我们将测试Perm1的增强 在SKM中的表达将阻止或加速SKM功能障碍的恢复。病毒和模型都在 手。 这项建议应该揭示与改善健康相关的重要基本信息和翻译信息 患有骨骼肌功能障碍的退伍军人是由于停用，更重要的是，是心力衰竭的结果。