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）萎缩是与肌肉废物相关的重大健康问题。它可以经常 与需要床休息或完全固定的任何类型的疾病或治疗相关。它可以 导致神经供应损伤或由慢性疾病（例如癌症，艾滋病，糖尿病，重要的是）造成的 该建议的重点，慢性心力衰竭（HF）。增加体育锻炼和运动减少肌肉萎缩 甚至通过导致SKM经历代谢，收缩和形态适应的来加速其恢复。 这些适应依赖于导致基因表达和酶促活性变化的信号通路。 因此，了解肌肉活性引起的信号传导的分子机制可能会提供 有关肌肉功能和适应的新型基本信息，并最终可以为 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已被证明是通过运动诱导和激活的， 并调节肌肉代谢程序。通过使用带有Myotube模型的微阵列屏幕。 PGC-1（Ppargamma共激活因子1）和ERR（与雌激素相关的受体）转录因子，我们鉴定了A 新颖的PGC-1 / ERR靶基因称为PERM1（PGC-1和ERR诱导的调节剂，肌肉1）。我们出版了 初步数据表明，条纹肌肉蛋白（PERS1）会影响肌肉生物能力，这是由 运动，调节代谢基因的表达，并修饰肌肉线粒体（mito）生物发生。 perm1 在SKM中也下调了，因为没有废除和心力衰竭的存在。 基于此强大的初步数据，我们提出了一个中心假设，即Perm1综合活性诱导 信号并增强肌肉线粒体生物发生和功能。推论的是，Perm1通过 调节活性/收缩诱导的激酶信号传导（CAMKII，钙/钙调蛋白依赖性蛋白激酶 ii）。通过活性引起的信号积分，PERS1可能会阻止废弃和HF诱导的SKM功能障碍。 为了解决这一假设，我们生成了两个新型鼠标模型，其中Perm1是特异性的 骨骼肌增加（perm1skmtransgenic（TG））或从骨骼肌中删除（Perm1Skm敲除 （KO））。以下具体目的将提出这一假设： AIM 1。研究PERS1在肌肉废物引起的代谢和功能改变中的作用。我们将 使用Perm1skmtg和Perm1skmko小鼠直接评估基本和病理状态下的Perm1功能 包括神经支配和铸造固定。 AIM 2。研究PERS1在心力衰竭引起的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小鼠进行了比较。我们假设 Perm1skmtg将受到HF诱导的SKM弱点和运动的保护，而Perm1skmko 小鼠将容易受到HF诱导的代谢和功能放松管制的影响。 perm1的机制 发生效果，在此目标中将追求与CAMKII相关的信号传导。 AIM 3。测试PERM1治疗因废药和心脏引起的SKM功能障碍的治疗益处 使用基因治疗方法的失败。这个目标将扩展到翻译工作，并测试如何改变 PERS1使用腺相关病毒（AAV）介导的基因治疗方法影响肌肉功能 PERS1在改善SKM功能障碍中的治疗潜力。我们将测试perm1的增强 SKM中的表达将防止或加速SKM功能障碍的恢复。病毒和模型都在 手。 该建议应揭示重要的基本和翻译的信息，以改善 由于心力衰竭而导致的残疾人，具有骨骼肌功能障碍的退伍军人。