Modulation of Muscle Regenerationby Growth Factors

生长因子对肌肉再生的调节

• 批准号: 8259528
• 负责人: Elisabeth R Barton
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-21 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259528
• 关键词: Acute; Alternative Splicing; Bone remodeling; C-terminal; Cell Proliferation; Cells; Chronic; Data; Dystrophin; Elderly; Exposure to; Extracellular Matrix; Fiber; Gene Targeting; Genes; Genetic; Goals; Grant; Growth; Growth Factor; Hereditary Disease; Histocompatibility Testing; In Vitro; Injury; Insulin-Like Growth Factor I; Link; Matrix Metalloproteinases; Measurement; Mediating; Mitotic; Muscle; Muscle Cells; Muscle Fibers; Muscle rehabilitation; Muscular Dystrophies; Myoblasts; Myopathy; Natural regeneration; New Agents; Nuclear; Patients; Peptides; Play; Population; Process; Production; Protein Isoforms; Regulation; Reporter; Resolution; Rodent; Role; Signal Transduction; Site; Skeletal Muscle; Source; Spliced Genes; Staging; Stem cells; Symptoms; Testing; Transgenic Mice; Tumor Cell Invasion; Viral; Wound Healing; base; cell motility; cell type; collagenase 3; improved; in vivo; interest; mdx mouse; migration; muscle regeneration; novel; peptide E (adrenal medulla); promoter; public health relevance; repaired; sarcopenia; satellite cell; therapeutic target

DESCRIPTION (provided by applicant): Skeletal muscle repair is a central therapeutic target for the muscular dystrophies, sarcopenia, and muscle rehabilitation after disuse or acute injury. Because muscle fibers are post-mitotic, repair must rely on satellite cells, a stem cell-like population residing close to muscle fibers as a source for replenishing nuclear content of the muscle. The ability and efficiency of satellite cell proliferation, differentiation, migration, and fusion to sites of injury are all important steps in the resolution of damage. IGF-I has long been recognized as one of the critical factors for regulating satellite cell actions during muscle regeneration, helping to repair damaged regions of the fibers, and to promote muscle growth. There is now a growing interest in the characterization of additional potentially active peptides produced by the igf1 gene. Alternative splicing of the gene results in multiple isoforms that retain the identical sequence for mature IGF-I, but also give rise to divergent C-terminal sequences, called the E-peptides. Recent evidence from our lab demonstrates that the E- peptide extensions directly regulate critical steps in muscle repair. First, the rodent EA and EB peptides stimulate proliferation of muscle cells in culture, potentially increasing the number of satellite cell available for repair. Second, the EA-peptide enhances expression and secretion of IGF-I during differentiation. Third, the EB-peptide regulates expression of matrix metalloproteinases, specifically MMP-13 in an IGF-I independent manner. In other tissue types, MMP-13 activity is a key regulator of wound healing, bone remodeling, and tumor invasion, as well as a modulator of additional MMP activity. Therefore, MMP-13 may improve muscle repair by enhancing satellite cell migration through the extracellular matrix, and by coordinating matrix remodeling around newly formed muscle fibers. Preliminary measurements of MMP-13 expression during muscle regeneration show that it is elevated during later stages of repair after fibers have begun to form. Further, MMP-13 expression is higher in muscles from the mdx mouse, where the absence of dystrophin leads to increased cycles of degeneration and regeneration. These studies suggest that MMP-13 is important component of muscle repair. The goals of this grant are (1) to determine if MMP-13 can accelerate proper resolution of muscle damage associated with genetic disease and after acute injury, and (2) to understand the functional links between IGF- I, the E peptides and MMP-13 activity. The mechanisms underlying their actions are essential to understand so that repair-enhancing therapies based on their functions can be developed. PUBLIC HEALTH RELEVANCE: Skeletal muscle repair occurs after acute injury and is an ongoing symptom associated with genetic muscle disease, specifically in the muscular dystrophies. Therefore, the therapies that enhance muscle regeneration can benefit patients suffering from genetic disease, those recovering from muscle injury, and the elderly. Understanding the mechanisms underlying muscle regeneration is of primary importance so that new agents can be developed to aid in the repair process.

描述（由申请人提供）：骨骼肌修复是肌肉营养不良，肌肉减少症和肌肉康复后的中心治疗靶标。由于肌肉纤维是有丝分裂后的，因此维修必须依靠卫星细胞，卫星细胞像干细胞一样，居住在肌肉纤维附近，作为补充肌肉核含量的来源。卫星细胞增殖，分化，迁移和融合到伤害部位的能力和效率都是解决损害的重要步骤。长期以来，IGF-I被认为是调节肌肉再生期间卫星细胞作用的关键因素之一，有助于修复纤维的受损区域并促进肌肉生长。现在，对IGF1基因产生的其他潜在活性肽的表征越来越兴趣。基因的替代剪接会导致多种同工型保留成熟IGF-I的相同序列，但也会引起不同的C末端序列，称为E肽。我们实验室的最新证据表明，e-肽延伸直接调节肌肉修复的关键步骤。首先，啮齿动物EA和EB肽在培养中刺激肌肉细胞的增殖，可能增加可修复的卫星细胞数量。其次，EA肽在分化过程中增强了IGF-I的表达和分泌。第三，EB肽调节基质金属蛋白酶的表达，特别是以IGF-1独立的方式MMP-13。在其他组织类型中，MMP-13活性是伤口愈合，骨骼重塑和肿瘤侵袭的关键调节剂，也是其他MMP活性的调节剂。因此，MMP-13可以通过增强卫星细胞通过细胞外基质的迁移，以及通过在新形成的肌肉纤维周围进行协调基质来改善肌肉修复。 MMP-13表达在肌肉再生过程中的初步测量表明，在纤维开始形成后修复后的后期阶段升高。此外，在MDX小鼠的肌肉中，MMP-13表达较高，其中缺乏肌营养不良蛋白会导致变性和再生周期增加。这些研究表明，MMP-13是肌肉修复的重要组成部分。该赠款的目标是（1）确定MMP-13是否可以加速与遗传疾病和急性损伤相关的肌肉损伤，以及（2）了解IGF-I，E肽和MMP之间的功能联系-13活动。其行为基础的机制对于理解至关重要，因此可以根据其功能开发基于其功能的维修增强疗法。 公共卫生相关性：急性损伤后发生骨骼肌修复，是与遗传肌肉疾病有关的持续症状，特别是在肌肉营养不良中。因此，增强肌肉再生的疗法可以使患有遗传疾病的患者，从肌肉损伤中康复的患者和老年人受益。了解肌肉再生的基础机制至关重要，因此可以开发出新的药物来帮助维修过程。