Modulation of Muscle Regenerationby Growth Factors

生长因子对肌肉再生的调节

• 批准号: 8097454
• 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/8097454
• 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）：骨骼肌修复是肌营养不良、肌肉减少症以及废用或急性损伤后肌肉康复的核心治疗目标。由于肌肉纤维是有丝分裂后的，因此修复必须依赖于卫星细胞，这是一种靠近肌肉纤维的干细胞样群体，作为补充肌肉核含量的来源。卫星细胞增殖、分化、迁移和融合到损伤部位的能力和效率都是解决损伤的重要步骤。 IGF-I 长期以来被认为是肌肉再生过程中调节卫星细胞活动的关键因素之一，有助于修复纤维受损区域并促进肌肉生长。现在人们对 igf1 基因产生的其他潜在活性肽的表征越来越感兴趣。基因的选择性剪接会产生多种亚型，这些亚型保留了成熟 IGF-I 的相同序列，但也产生了不同的 C 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 肽刺激培养物中肌肉细胞的增殖，可能增加可用于修复的卫星细胞的数量。其次，EA-肽在分化过程中增强IGF-I的表达和分泌。第三，EB肽以独立于IGF-I的方式调节基质金属蛋白酶，特别是MMP-13的表达。在其他组织类型中，MMP-13 活性是伤口愈合、骨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穿过细胞外基质的迁移以及协调新形成的肌纤维周围的基质重塑来改善肌肉修复。肌肉再生过程中 MMP-13 表达的初步测量表明，在纤维开始形成后的修复后期阶段，MMP-13 表达升高。此外，mdx 小鼠的肌肉中 MMP-13 表达较高，其中肌营养不良蛋白的缺乏导致退化和再生周期增加。这些研究表明 MMP-13 是肌肉修复的重要组成部分。这笔资助的目标是 (1) 确定 MMP-13 是否可以加速与遗传性疾病和急性损伤后相关的肌肉损伤的正确解决，以及 (2) 了解 IGF-I、E 肽和 MMP-13 活性之间的功能联系。了解其作用机制至关重要，以便开发基于其功能的修复增强疗法。 公共卫生相关性：骨骼肌修复发生在急性损伤后，是与遗传性肌肉疾病（特别是肌营养不良症）相关的持续症状。因此，增强肌肉再生的疗法可以使患有遗传性疾病的患者、从肌肉损伤中恢复的患者以及老年人受益。了解肌肉再生的机制至关重要，以便开发新的药物来帮助修复过程。