NO-dependent SOD3 protection against cachexia

描述（由申请人提供）：恶病质是许多慢性疾病的严重疾病，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，在美国每年影响约600万人。它的特点是肌肉量减少（分解代谢消耗），经常导致运动能力下降（运动不耐受）和死亡。由活性氧（ROS）的过量产生和随之而来的细胞损伤引起的骨骼肌异常是这些有害条件的基础。众所周知，氧化肌肉能够抵抗分解代谢消耗；然而，潜在的机制仍然难以捉摸。我们最近在一个CHF（心脏特异性钙调蛋白（CSQ）转基因小鼠）小鼠模型中表明，骨骼肌中这种氧化表型相关的保护是由于一氧化氮（NO）依赖的抗氧化防御，可能通过激活Keap1/Nrf2支架蛋白转录因子复合物，而快速收缩的糖酵解肌缺乏这种保护机制，容易受到病毒质刺激。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可提高SOD3的表达并减少糖酵解肌肉的分解代谢消耗。这些发现表明骨骼肌中no - sod3依赖性防御的功能重要性，这可能不仅是与氧化表型相关的保护的基础，也是耐力运动训练的有益影响。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。为了验证这一假设，我们提出：1)确定SOD3在骨骼肌中对CHF分解代谢消耗和运动不耐受的功能作用；2)阐明no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而重要的细胞防御机制。这些研究可能为与许多慢性疾病相关的肌肉萎缩和运动不耐受的更有效治疗提供新的信息。

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.