Modulation of Muscle Regenerationby Growth Factors

描述（由申请人提供）：骨骼肌修复是肌营养不良症、肌肉减少症和废弃或急性损伤后肌肉康复的中心治疗靶点。因为肌纤维是有丝分裂后的，修复必须依靠卫星细胞，一种靠近肌纤维的干细胞样细胞群，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。长期以来，igf - 1一直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，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感兴趣。基因的选择性剪接产生了多个同种异构体，这些异构体保留了成熟的igf - 1的相同序列，但也产生了不同的c端序列，称为e肽。我们实验室最近的证据表明，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肽刺激培养肌肉细胞的增殖，潜在地增加可用于修复的卫星细胞的数量。其次，ea肽在分化过程中促进了igf - 1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，也是额外MMP活性的调节剂。因此，MMP-13可能通过增强卫星细胞通过细胞外基质的迁移，以及通过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，MMP-13表达水平升高。此外，MMP-13在mdx小鼠肌肉中的表达更高，其中缺乏肌营养不良蛋白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。这项资助的目的是：(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的适当解决，(2)了解IGF- I、E肽和MMP-13活性之间的功能联系。了解它们的作用机制至关重要，这样才能开发出基于其功能的修复增强疗法。

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.