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: 10618851
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618851
• 关键词: Acceleration; 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; Genes; Hand; Health; Heart; Heart Diseases; Heart failure; Immobilization; Injury; Knock-out; 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; Predisposition; Protein Kinase; Publishing; Recovery; Role; Signal Induction; Signal Pathway; Signal Transduction; Skeletal Muscle; Striated Muscles; Testing; Transcription Coactivator; Veterans; Virus; Work; aorta constriction; calmodulin-dependent protein kinase II; clinical application; 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.

项目概要/摘要 骨骼肌（SkM）萎缩是与肌肉废用相关的重大健康问题。可以经常 与需要卧床休息或完全制动的任何类型的疾病或治疗有关。它可以 神经供应损伤或慢性疾病，如癌症、艾滋病、糖尿病，更重要的是， 该提案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导的分子机制可能会提供 关于肌肉功能和适应的新颖的基本信息，最终可以提供新的方法 治疗肌肉功能障碍，包括心力衰竭引起的肌肉功能障碍。 我们注意到转录共激活因子 PGC-1 已被证明可以通过运动诱导和激活， 并调节肌肉代谢程序。通过使用微阵列屏幕和肌管模型转导 PGC-1（PPARgamma 共激活因子 1）和 ERR（雌激素相关受体）转录因子，我们鉴定了 新的 PGC-1 / ERR 靶基因，称为 Perm1（PGC-1 和 ERR 诱导调节因子，肌肉 1）。我们发表的 初步数据表明，横纹肌蛋白 (Perm1) 影响肌肉生物能，是由 锻炼、调节代谢基因的表达并改变肌肉线粒体 (Mito) 的生物合成。烫发1 在 SkM 中，随着废用和心力衰竭的存在，该蛋白也会下调。 基于这些强有力的初步数据，我们提出了中心假设：Perm1 整合了活动诱导的 发出信号并增强肌肉线粒体的生物发生和功能。由此推论，Perm1 的作用是 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 二）。通过活动诱导的信号整合，Perm1 可以预防废用和 HF 诱导的 SkM 功能障碍。 为了解决这个假设，我们生成了两种新的小鼠模型，其中 Perm1 是特异性的 骨骼肌中增加（Perm1SkMTransgenic (TG)）或骨骼肌中缺失（Perm1SkM 敲除 （KO））。这一假设将通过以下具体目标来实现： 目标 1. 研究 Perm1 在肌肉废用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Perm1在基础和病理状态下的功能 包括去神经支配和石膏固定。 目标 2. 研究 Perm1 在心力衰竭引起的 SkM 功能障碍中的作用。我们来研究一下Perm1的作用 在 HF 诱导的 SkM 功能障碍中，将 WT 小鼠与 Perm1SkMTG 和 Perm1SkMKO 小鼠进行比较。我们假设 Perm1SkMTG 将免受 HF 引起的 SkM 无力和运动不耐受的影响，而 Perm1SkMKO 小鼠容易受到心力衰竭引起的代谢和功能失调的影响。 Perm1 的机制 效应发生时，例如 CaMKII 相关信号传导将在此目标下进行。 目标 3. 测试 Perm1 对治疗废用性和心脏引起的 SkM 功能障碍的治疗效果 使用基因治疗方法失败。这一目标将扩展到翻译工作并测试如何改变 使用腺相关病毒（AAV）介导的基因治疗方法来测试 Perm1 对肌肉功能的影响 Perm1 在改善 SkM 功能障碍方面的治疗潜力。我们将测试 Perm1 是否增强 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。 该提案应揭示与改善健康相关的重要基础信息和转化信息 患有骨骼肌功能障碍的退伍军人因停用而出现，更重要的是，由于心力衰竭而出现。