NO-dependent SOD3 protection against cachexia

NO 依赖性 SOD3 预防恶病质

• 批准号: 8240334
• 负责人: Zhen Yan
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240334
• 关键词: Affect; Antioxidants; Attenuated; Binding; Bioluminescence; Cachexia; Calsequestrin; Cardiac; Cessation of life; Chronic Disease; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Communicable Diseases; Complex; Congestive Heart Failure; Cysteine; Data; Defense Mechanisms; Dependovirus; Dissociation; Enzymes; Exercise; Exhibits; Gene Expression; Gene Transfer; Genes; Heart Block; Image; Knock-out; Knockout Mice; Malignant Neoplasms; Maps; Mediating; Medical; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Mutation; NF-E2-related factor 2; Nitric Oxide; Nitric Oxide Donors; Phenotype; Physiologic pulse; Process; Production; Reactive Oxygen Species; Resistance; Response Elements; Role; Scaffolding Protein; Serine; Site; Skeletal Muscle; Stimulus; Superoxide Dismutase; Testing; Therapeutic; Tissues; Training; Transactivation; Transgenic Mice; Work; extracellular; gain of function; in vivo; loss of function; mortality; mouse model; muscle form; muscular structure; mutant; novel; overexpression; prevent; promoter; protein complex; transcription factor; wasting

DESCRIPTION (provided by applicant): Cachexia is a serious medical condition in many chronic diseases, such as cancer, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), chronic kidney disease (CKD) and some infectious diseases, affecting about 6 million people in the U.S. annually. It is characterized by loss of muscle mass (catabolic wasting) and often leads to reduced exercise capacity (exercise intolerance) and mortality. Skeletal muscle abnormalities caused by excess production of reactive oxygen species (ROS) and the consequent cellular damages underlie these detrimental conditions. It is well known that oxidative muscles are resistant to catabolic wasting; however, the underlying mechanisms remain elusive. We have shown recently in a mouse model of CHF [cardiac-specific calsequestrin (CSQ) transgenic mice] that this oxidative phenotype-associated protection in skeletal muscle is due to a nitric oxide (NO)-dependent antioxidant defense possibly through activation of the Keap1/Nrf2 scaffold protein-transcription factor complex, whereas fast-twitch glycolytic muscles lack such a protective mechanism and are vulnerable to cachectic stimuli. Our preliminary data shows that extracellular superoxide dismutase (EcSOD or SOD3) is highly expressed in oxidative and exercise- trained muscles, and augmenting NO enhances SOD3 expression and reduces catabolic wasting in glycolytic muscles. These findings indicate the functional importance of this NO-SOD3-dependent defense in skeletal muscle, which may underlie not only the protection associated with the oxidative phenotype, but also the salutary impact of endurance exercise training. We hypothesize that NO protects skeletal muscle from catabolic wasting through activation of the Keap1/Nrf2 protein complex and induction of SOD3 expression. To test this hypothesis, we propose: 1) To ascertain the functional role of SOD3 in skeletal muscle against catabolic wasting and exercise intolerance in CHF; and 2) To elucidate the "molecular switch" in the NO-dependent antioxidant defense. If our hypothesis proves to be correct, we will have uncovered a novel and important cellular defense mechanism in skeletal muscle. The studies may provide new information for more effective therapeutics for muscle wasting and exercise intolerance associated with numerous chronic diseases. PUBLIC HEALTH RELEVANCE: Cachexia (severe loss of muscle mass), a serious medical condition for many chronic diseases, often leads to inability to exercise and death. We have found that skeletal muscles that make more extracellular superoxide dismutase, EcSOD (SOD3) are protected from cachexia. Here we propose studies to find out whether SOD3 is functionally important in protecting muscle structure and function in cardiac cachexia and how SOD3 production is increased in those skeletal muscle that are protected.

描述（由申请人提供）：恶病质是许多慢性疾病中的一种严重疾病，例如癌症、慢性阻塞性肺病 (COPD)、充血性心力衰竭 (CHF)、慢性肾病 (CKD) 和一些传染病，每年影响约 600 万人在美国。其特征是肌肉质量损失（分解代谢消耗），并且常常导致运动能力降低（运动不耐受）和死亡率。活性氧 (ROS) 产生过量导致骨骼肌异常以及随之而来的细胞损伤，这些都是这些有害状况的根源。众所周知，氧化性肌肉能够抵抗分解代谢消耗。然而，根本机制仍然难以捉摸。我们最近在 CHF 小鼠模型（心脏特异性钙螯合蛋白 (CSQ) 转基因小鼠）中证明，骨骼肌中这种与氧化表型相关的保护是由于一氧化氮 (NO) 依赖性抗氧化防御，可能是通过激活 Keap1/Nrf2 支架蛋白转录因子复合物来实现的，而快肌糖酵解肌缺乏这种氧化防御机制。 保护机制，容易受到恶病质刺激。我们的初步数据表明，细胞外超氧化物歧化酶（EcSOD 或 SOD3）在氧化和运动训练的肌肉中高度表达，增加 NO 可以增强 SOD3 表达并减少糖酵解肌肉中的分解代谢消耗。这些发现表明骨骼肌中这种 NO-SOD3 依赖性防御的功能重要性，这不仅可能是与氧化表型相关的保护的基础，而且也是耐力运动训练的有益影响的基础。我们假设 NO 通过激活 Keap1/Nrf2 蛋白复合物和诱导 SOD3 表达来保护骨骼肌免受分解代谢消耗。为了检验这一假设，我们建议：1) 确定 SOD3 在骨骼肌中对抗 CHF 分解代谢消耗和运动不耐受的功能作用； 2) 阐明一氧化氮依赖性抗氧化防御中的“分子开关”。如果我们的假设被证明是正确的，我们将在骨骼肌中发现一种新颖且重要的细胞防御机制。这些研究可能为更有效地治疗与多种慢性疾病相关的肌肉萎缩和运动不耐受提供新信息。 公共卫生相关性：恶病质（肌肉质量严重丧失）是许多慢性疾病的一种严重疾病，常常导致无法运动和死亡。我们发现，产生更多细胞外超氧化物歧化酶 EcSOD (SOD3) 的骨骼肌可以免受恶病质的影响。在这里，我们提出研究来查明 SOD3 在保护心脏恶病质中的肌肉结构和功能方面是否具有重要功能，以及 SOD3 的产生如何在受保护的骨骼肌中增加。