Role of skeletal muscle stem cell fusion and fibrosis during aging

项目总结/摘要 肌肉减少症是一种毁灭性的骨骼肌状况，发生在老年人和由于各种慢性 条件尽管肌肉减少症广泛流行，但没有治疗选择， 这一过程的基本机制尚未完全了解。骨骼特征 肌肉老化是肌纤维大小和数量减少，肌肉功能失调， 纤维化的发病率。在衰老过程中改变的另一个过程是肌肉干细胞（MuSC）的活性， 其通常是静止的，但在年轻的环境中起作用，以完全修复受损的肌肉， 肌肉适应外界刺激。虽然MuSC显然是发育和再生所必需的， 我们仍然不了解它们在肌肉稳态和衰老过程中的确切作用。为此我们 产生了一种独特的小鼠模型，该模型消除了MuSC融合活性，但保持了它们在细胞内的存在。 组织.我们最近的研究表明，MuSC融合是年轻环境中肌肉生长所必需的， 而没有MuSC融合，则纤维化增强的显著发展。此外，我们的初步数据 表明MuSC融合在老化骨骼肌中失调。因此，我们假设， 具有肌纤维的MuSC是维持肌纤维完整性所必需的，并且该过程的失调导致 衰老过程中病理性细胞外基质（ECM）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MuSC融合和纤维化。基于 根据这些初步数据和独特的小鼠模型，我们建议全面确定 MuSC和评估骨骼肌老化过程中纤维化发展的后果。我们特别 建议：1）从分子角度阐明MuSC融合对衰老期间肌肉适应的要求2） 分析老年骨骼肌融合的机制; 3）明确纤维化与骨骼肌纤维化之间的关系。 肌肉减少症发展过程中的MuSC融合。成功完成这些研究将提供独特的 深入了解MuSC依赖性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肌肉减少症。

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.