ECM and MMPs in Muscle Atrophy and Rehabilitation

描述(由申请人提供)： 摘要骨骼肌萎缩是制动、神经损伤和肌肉骨骼损伤(如肌腱损伤)后的常见并发症。年龄较大的患者尤其容易受到影响，应对后果的能力要差得多。尽管它具有明显的临床重要性，但肌肉萎缩的病理生物学仍然知之甚少，目前还没有可用的药物治疗方法。在我们的初步研究中，我们观察到跟腱横断后腓肠肌迅速和可预测的萎缩，这与基质金属蛋白酶-2的上调有关，基质金属蛋白酶是细胞外基质降解和重塑的关键酶。我们发现，与野生型对照相比，肌腱横断后，MMP-2基因缺失的小鼠肌肉萎缩和基质降解明显减少。此外，我们发现，与年轻小鼠相比，基质金属蛋白酶-2的缺失对老年小鼠肌肉萎缩的影响要大得多。有趣的是，我们的初步实验还表明，在神经损伤引起的肌肉萎缩期间，基质金属蛋白酶-2表达上调，但在四肢悬吊导致的肌肉萎缩期间，却没有上调。提示在不同的肌萎缩模型中，基质金属蛋白酶-2活性在肌萎缩病理生物学中的意义可能不同。因此，在我们提出的研究中，我们将使用与军事和退伍军人群体特别相关的三种小鼠模型，全面分析基质金属蛋白酶-2在体内肌肉萎缩关键指标中的功能作用-肌腱损伤后的肌肉萎缩、神经损伤和肢体卸载。然后，我们将使用一系列转基因小鼠来确定在肌肉萎缩中导致基质金属蛋白酶-2表达增加的调控网络。将使用老年小鼠进行平行实验，以确定基质金属蛋白酶-2在肌肉萎缩发病机制中的作用随年龄的变化。最后，我们将测试针对基质金属蛋白酶-2的特定抑制剂可以减少或防止肌肉萎缩的假设，至少在观察到基质金属蛋白酶-2显著活性的模型中是这样。我们相信，从这项研究中获得的新信息将极大地帮助我们理解基质金属蛋白酶-2与肌肉萎缩之间的关系，并可能进一步导致旨在治疗骨骼肌萎缩的新的治疗方法。 公共卫生相关性： 相关性：与私营部门相比，退伍军人病患群体由于多种因素，特别是发生肌肉萎缩的风险很高，包括患者年龄、严重的合并症以及较长的住院时间[Rosenthal，2003]。上了年纪的退伍军人特别容易出现肌肉萎缩，并因此遭受更大的残疾。鉴于VA患者群体中老年人数的预计增加，骨骼肌萎缩将成为一个更严重的问题。该项目的成功完成将确定一种重要的细胞外基质降解酶在这种常见肌肉疾病中的作用和调节。这项研究的结果将导致新的治疗方法，旨在治疗骨骼肌萎缩，这是为老年退伍军人患者量身定做的。因此，我们的建议对退伍军人群体具有特殊的意义。

DESCRIPTION (provided by applicant): Abstract Skeletal muscle atrophy is a common complication following immobilization, nerve injury, and musculoskeletal trauma such as tendon injuries. Older patients are especially susceptible and are far less able to cope with the consequences. In spite of its obvious clinical importance, the pathobiology of muscle atrophy remains poorly understood, and no pharmacologic treatments are currently available. In our preliminary study, we have observed rapid and predictable atrophy of the gastrocnemius muscle after Achilles tendon transection, which is associated with up-regulation of MMP-2, a key enzyme responsible for ECM degradation and remodeling. We discovered that MMP-2 null mice undergo markedly less muscle atrophy and matrix degradation compared to wild type controls after tendon transection. Furthermore, we found that loss of MMP-2 has a much greater impact on muscle atrophy in older mice than it does in younger mice. Interestingly, our pilot experiments also show that MMP-2 is upregulated during muscle atrophy resulting from nerve injury, but not during muscle atrophy resulting from limb suspension. This data suggests that the significance of MMP-2 activity in pathobiology of muscle atrophy may vary between different muscle atrophy models. Thus, in our proposed study, we will comprehensively analyze the functional role of MMP-2 on key measures of muscle atrophy in vivo using three mouse models with particular relevance to military and VA populations-muscle atrophy following tendon injury, nerve injury and limb unloading. We will then use a series of transgenic mice to define the regulatory networks responsible for increased MMP-2 expression in muscle atrophy. Parallel experiments will be performed using older mice to identify age-dependent changes in the role for MMP-2 in the pathogenesis of muscle atrophy. Finally, we will test the hypothesis that specific inhibitors targeted at MMP-2 can decrease or prevent muscle atrophy, at least in models where significant activity of MMP-2 is observed. We believe novel information gained from this study will greatly help us in understanding the relationship between MMP-2 and muscle atrophy and may further lead to new therapeutic approaches designed to treat skeletal muscle atrophy. PUBLIC HEALTH RELEVANCE: Relevance The VA patient population, in particular, is at high risk for developing muscle atrophy due to a wide range of factors including patient age, significant co-morbidities, and lengthier hospitalizations compared to the private sector [Rosenthal, 2003]. Aged veterans are especially susceptible to muscle atrophy and suffer much greater disability as a result. Given the projected rise in the number of elderly in the VA patient population, skeletal muscle atrophy will become an even greater problem. Successful achievement of this project will define the role and regulation of an important extracellular matrix degradation enzyme in this common muscle disorder. Results from this study will lead to new therapeutic approaches designed to treat skeletal muscle atrophy, which are tailored for the elderly veteran patients. Therefore, our proposal has particular significance for the VA population.