NO-dependent SOD3 protection against cachexia

NO 依赖性 SOD3 预防恶病质

• 批准号: 8331375
• 负责人: Zhen Yan
• 金额: $ 17.33万
• 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/8331375
• 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.

描述(申请人提供)：恶病质是许多慢性疾病的一种严重疾病，如癌症、慢性阻塞性肺疾病(COPD)、充血性心力衰竭(CHF)、慢性肾脏疾病(CKD)和一些传染病，每年在美国约有600万人受到影响。它的特点是肌肉质量下降(分解代谢损耗)，并经常导致运动能力降低(运动耐受)和死亡。这些有害的情况是由过量产生活性氧基(ROS)引起的骨骼肌异常和随之而来的细胞损伤所致。众所周知，氧化肌肉对分解代谢的消耗具有抵抗力；然而，其潜在的机制仍然难以捉摸。我们最近在CHF[心脏特异性钙调素(CSQ)转基因小鼠]的小鼠模型中表明，骨骼肌中的这种氧化表型相关保护是由于一氧化氮(NO)依赖的抗氧化防御，可能是通过激活Keap1/Nrf2支架蛋白-转录因子复合体，而快速抽动的糖酵解肌肉缺乏这种保护机制，并且容易受到恶病质刺激的影响。我们的初步数据显示，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的表达，减少糖酵解肌肉中分解代谢的消耗。这些发现表明了骨骼肌中这种NO-SOD3依赖的防御功能的重要性，这可能不仅是与氧化表型相关的保护作用，也是耐力运动训练的有益影响。我们推测，NO通过激活Keap1/Nrf2蛋白复合体和诱导SOD3的表达来保护骨骼肌免受分解代谢的消耗。为了验证这一假说，我们建议：1)确定骨骼肌SOD3在CHF中对抗分解代谢消耗和运动耐量的功能作用；2)阐明NO依赖的抗氧化防御中的“分子开关”。如果我们的假设被证明是正确的，我们将发现骨骼肌中一种新颖而重要的细胞防御机制。这些研究可能会为更有效地治疗与多种慢性病相关的肌肉萎缩和运动不耐受提供新的信息。