Replicative Potential of Muscle Stem Cells

项目摘要 骨骼肌组织得到维护，并可通过以下变化动态建模以适应持续的需求 肌肉活动。肌纤维是构成骨骼肌收缩元素的主要细胞，它是 有丝分裂后，由被称为卫星细胞的干细胞池维持，这些干细胞定位于一个利基- 在肌纤维和覆盖的基底板之间。骨骼肌功能丧失所致的活动能力丧失 发生在受伤后，是衰老的必然结果，也是许多神经肌肉的结果 疾病，后两种导致生活质量下降和发病率增加，需要住院或 家庭护理，大大提高了医疗保健成本。这些复杂的生理变化是有据可查的 但导致这些变化的机制尚不清楚。 SCS(卫星细胞)在整个生命过程中维持肌肉，为新的肌核提供持续的来源 似乎主要是通过不对称分裂发生的。SC不对称分裂的丧失导致与年龄相关的 衰老过程中SC功能的丧失和营养不良的肌肉表型。增强供应链的应对能力 VIDE不对称地提高衰老肌肉的力量，改善营养不良的肌肉功能。依赖于- 骨骼肌健康对干细胞维持的影响，这反过来要求干细胞不对称地分裂为- 调整SC不对称部门的关键角色，这一问题尚未得到充分解决。表皮生长因子受体(表皮 生长因子受体)和FGFR1信号促进干细胞不对称分裂，将其识别为两个 参与维持干细胞的关键信号通路。EGFR信号通路的激活可改善营养不良 老年肌肉SCs的肌肉表型和FGFR1信号的激活拯救不对称分裂 使衰老小鼠的SC数量恢复到年轻水平并增加力量，表明SC不对称 分裂是维持骨骼肌健康的关键。拟议中的实验的主要前提是 这一应用是推动干细胞不对称分裂，改善肌肉健康。但是，SC包括一个 骨骼肌中的少量细胞(1-3%)，因此，SC健康的改善如何影响 整个肌肉？为了填补这一知识鸿沟，我们计划确定推动SC划分不对称的途径。 计算并阐明刺激SC不对称分裂增强骨骼肌的机制 功能。

Project Summary Skeletal muscle tissue is maintained and can be dynamically modeled to fit ongoing needs by changes in muscular activity. Myofibers, the primary cells that comprise the contractile elements of skeletal muscle, are post-mitotic and maintained by a pool of stem cells, termed satellite cells, which are localized to a niche be- tween the myofiber and overlying basal lamina. Loss of mobility arising from loss of skeletal muscle function occurs following an injury, is an inevitable consequence of aging and a consequence of many neuromuscular diseases, the latter two resulting in reduced quality of life and increased morbidity, requiring hospitalization or home care, significantly raising health care costs. These complex physiological changes are well documented but the mechanisms responsible for these changes are not understood. SCs (satellite cells) maintain muscle throughout life, providing a constant source of new myonuclei that appears to occur primarily by asymmetric division. Loss of SC asymmetric division contributes to age-related losses of SC function during aging and to the dystrophic muscle phenotype. Enhancing the ability of SCs to di- vide asymmetrically improves strength in aged muscle and improves dystrophic muscle function. The depend- ence of skeletal muscle health on SC maintenance, which in turn requires SCs divide asymmetrically empha- sizes an essential role for SC asymmetric division that has not been adequately addressed. EGFR (epidermal growth factor receptor) and FGFR1 signaling promote SCs to divide asymmetrically, identifying these as two critical signaling pathways involved in maintaining SCs. Activation of EGFR signaling improves dystrophic muscle phenotypes and activation of FGFR1 signaling in SCs from aged muscle rescues asymmetric division restoring SC numbers to youthful levels and increases strength in aged mice, suggesting that SC asymmetric division is essential to maintain skeletal muscle health. The primary premise for the proposed experiments in this application is that driving SCs to divide asymmetrically improves muscle health. However, SCs comprise a minor population of cells within skeletal muscle (1-3%) and thus, how can improvement of SC health affect an entire muscle? To fulfill this knowledge gap, we plan to identify the pathways driving SCs to divide asymmetri- cally and elucidate the mechanisms by which stimulation of SC asymmetric division enhances skeletal muscle function.