Role of skeletal muscle stem cell fusion and fibrosis during aging

项目摘要/摘要 骨质疏松症是一种毁灭性的骨骼肌疾病，发生在中老年，由各种慢性疾病引起 条件。尽管石棺减少症普遍流行，但没有治疗选择，而且 这一过程背后的机制还没有完全被理解。骨骼的标志特征 肌肉衰老是指肌肉纤维的大小和数量减少，肌肉功能失调，以及 肝纤维化的发生率。在衰老过程中改变的另一个过程是肌肉干细胞(MuSCs)的活动， 它们通常是静止的，但在年轻的环境中，它们的功能是完全修复受损的肌肉，并允许 肌肉能适应外界刺激。尽管MSC显然是发展和再生所必需的， 我们仍然不了解它们在肌肉动态平衡和衰老过程中的确切作用。为此，我们有 产生了一种独特的小鼠模型，该模型可以消除MUSC融合活动，但保持它们在 组织。我们最近的研究表明，在年轻的环境中，肌肉生长需要MUSC融合， 如果不进行骨髓间充质干细胞融合，就会出现明显的纤维化。此外，我们的初步数据 提示MUSC融合在衰老的骨骼肌中处于失调状态。因此，我们假设核聚变 含有肌纤维的肌间充质干细胞是维持肌纤维完整性所必需的，这一过程的失调导致 病理性细胞外基质(ECM)在衰老过程中的重塑。为了明确回答这些问题，我们 已经产生了许多新的遗传试剂来操纵体内的骨髓间充质干细胞融合和纤维化。基座 根据这些初步数据和独特的鼠标模型，我们建议全面确定 并评估骨骼肌衰老过程中纤维化发展的后果。具体来说，我们 建议：1)从分子角度阐明MUSC融合对衰老过程中肌肉适应的要求 解剖老年骨骼肌融合的机制和3)确定纤维化和 骨质疏松症发生过程中的MUSC融合。成功完成这些研究将提供独特的 深入了解MUSC依赖的肌肉衰老的一般机制，并提供新的知识 确定新的治疗策略来对抗石棺减少症。

Project Summary/Abstract Sarcopenia is a devastating skeletal muscle condition that occurs in advanced age and due to various chronic conditions. Despite the widespread prevalence of sarcopenia there are no treatment options and the mechanisms underlying this process are not completely understood. Hallmark characteristics of skeletal muscle aging are a reduction in myofiber size and number, dysregulated muscle function, and an increased incidence of fibrosis. An additional process altered during aging is the activity of muscle stem cells (MuSCs), which typically are quiescent but in a young environment function to fully repair damaged muscle and allow muscle to adapt to external stimuli. Although MuSCs are clearly required for development and regeneration, we still do not understand their exact role during muscle homeostasis and aging. To this end, we have generated a unique mouse model that ablates MuSC fusion activity but maintains their presence within the tissue. Our recent studies showed that MuSC fusion is required for muscle growth in a young environment, and that without MuSC fusion, pronounced development of fibrosis ensues. Moreover, our preliminary data indicate that MuSC fusion is dysregulated in aged skeletal muscle. Thus, we hypothesize that fusion of MuSCs with myofibers is necessary to maintain myofiber integrity, and dysregulation of this process leads to pathological extracellular matrix (ECM) remodeling during aging. To definitively answer these questions, we have generated numerous novel genetic reagents to manipulate both MuSC fusion and fibrosis in vivo. Based on these preliminary data and unique mouse models we propose to comprehensively determine the role for MuSCs and evaluate the consequences of fibrosis development during skeletal muscle aging. Specifically, we propose to: 1) elucidate the requirement of MuSC fusion for muscle adaptation during aging 2) molecularly dissect the mechanisms of fusion in aged skeletal muscle and 3) define the relationship between fibrosis and MuSC fusion during the development of sarcopenia. Successful completion of these studies will provide unique insight into the general mechanisms of MuSC-dependent muscle aging and provide new knowledge that will identify new therapeutic strategies to combat sarcopenia.