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）后常见的并发症。老年患者特别容易受到影响，远不能科普后果。尽管其明显的临床重要性，肌肉萎缩的病理生物学仍然知之甚少，目前没有可用的药物治疗。在我们的初步研究中，我们观察到跟腱切断后腓肠肌的快速和可预测的萎缩，这与MMP-2的上调有关，MMP-2是负责ECM降解和重塑的关键酶。我们发现，MMP-2基因敲除小鼠在肌腱横断后，与野生型对照组相比，肌肉萎缩和基质降解明显减少。此外，我们发现MMP-2的丢失对老年小鼠的肌肉萎缩的影响比年轻小鼠大得多。有趣的是，我们的初步实验还表明，MMP-2在神经损伤引起的肌肉萎缩期间上调，但在肢体悬吊引起的肌肉萎缩期间不上调。该数据表明，MMP-2活性在肌肉萎缩的病理生物学中的意义可能在不同的肌肉萎缩模型之间变化。因此，在我们提出的研究中，我们将全面分析MMP-2在体内肌肉萎缩的关键措施的功能作用，使用三种小鼠模型，特别是与军事和VA人群-肌腱损伤，神经损伤和肢体卸载后肌肉萎缩。然后，我们将使用一系列的转基因小鼠，以确定负责增加MMP-2的表达在肌肉萎缩的调控网络。将使用老年小鼠进行平行实验，以确定MMP-2在肌肉萎缩发病机制中的作用的年龄依赖性变化。最后，我们将测试的假设，针对MMP-2的特异性抑制剂可以减少或防止肌肉萎缩，至少在模型中观察到MMP-2的显着活性。我们相信从这项研究中获得的新信息将极大地帮助我们了解MMP-2和肌肉萎缩之间的关系，并可能进一步导致新的治疗方法，旨在治疗骨骼肌萎缩。

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.