ECM and MMPs in Muscle Atrophy and Rehabilitation

ECM 和 MMP 在肌肉萎缩和康复中的应用

• 批准号: 8898721
• 负责人: Hubert T. Kim
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898721
• 关键词: Achievement; Age; Animal Model; Atrophic; Binding; Binding Sites; Clinical; Comorbidity; Complication; Data; Denervation; Development; Elderly; Enzymes; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Family; Functional disorder; Gastrocnemius Muscle; Gelatinase A; Genes; Hindlimb Suspension; Homeostasis; Hospitalization; Immobilization; Introns; Knockout Mice; Lead; Limb structure; Matrix Metalloproteinases; Measures; Mediator of activation protein; Military Personnel; Modeling; Mus; Muscle; Muscle rehabilitation; Muscular Atrophy; Musculoskeletal; Myopathy; Pathogenesis; Patients; Pattern; Population; Private Sector; Promoter Regions; Regulation; Role; Series; Skeletal Muscle; Suspension substance; Suspensions; Tendon Injuries; Tendon structure; Testing; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; Trauma; Up-Regulation; Veterans; abstracting; achilles tendon; age effect; age related; aged; clinically relevant; coping; design; disability; high risk; in vivo; inhibitor/antagonist; mouse model; nerve injury; novel; novel therapeutic intervention; older patient; patient population; prevent; promoter; research study; transcription factor; treatment strategy

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.

描述（由申请人提供）： 摘要 骨骼肌萎缩是制动、神经损伤和肌腱损伤等肌肉骨骼创伤后的常见并发症。老年患者尤其容易受到影响，而且应对后果的能力要差得多。尽管肌肉萎缩具有明显的临床重要性，但其病理学仍然知之甚少，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快速且可预测的萎缩，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，与野生型对照相比，MMP-2 缺失小鼠在肌腱横断后经历的肌肉萎缩和基质降解明显较少。此外，我们发现 MMP-2 的缺失对老年小鼠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 在神经损伤导致的肌肉萎缩期间上调，但在肢体悬吊导致的肌肉萎缩期间则不会上调。该数据表明，MMP-2 活性在肌肉萎缩病理学中的重要性可能因不同肌肉萎缩模型而异。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 MMP-2 对体内肌肉萎缩关键指标的功能作用 - 肌腱损伤、神经损伤和肢体卸载后的肌肉萎缩。然后，我们将使用一系列转基因小鼠来定义负责肌肉萎缩中 MMP-2 表达增加的调节网络。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作用的年龄依赖性变化。最后，我们将测试以下假设：针对 MMP-2 的特定抑制剂可以减少或预防肌肉萎缩，至少在观察到 MMP-2 显着活性的模​​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了解 MMP-2 和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治疗方法。