Determining the fiber type-specific requirements for satellite cells during skeletal muscle hypertrophy

项目摘要/摘要 缺乏运动、高龄、四肢瘫痪、退行性疾病和各种全身性疾病 疾病(许多癌症、败血症、艾滋病毒、慢性阻塞性肺病、肾脏疾病)都会导致骨骼肌萎缩。损失的损失 肌肉质量具有重要的临床意义，因为它会增加发病率、残疾和 独立性的丧失；共同推动了医疗保健利用率和成本的大幅增加。一个 美国人口迅速老龄化无疑将导致骨质疏松症患病率的增加和年龄的增加- 引起恶病质的相关系统性疾病。为了减少随之而来的医疗费用增加， 开发促进健康衰老和延长功能独立性的干预策略是至关重要的。 对肌肉干细胞(卫星细胞)在肌肉中的作用有一个基本的了解 肥大将增加靶向这些细胞的可能性，并增强它们促进肌肉的能力 成长。我们的实验室此前表明，虽然缺乏卫星细胞并不会限制肌肉的短期生长， 卫星细胞需要支持持续的生长，至少在2型(快速抽动)纤维中是这样。补偿性的 在没有卫星细胞融合的情况下激活的通路，使2型纤维中的肌肉短期生长 都是有意义的。与此相一致，促使对卫星细胞需求的转变的机制在 肌肉的持续生长是未知的。由于以前研究中使用的过载方法，我们的 对卫星细胞介导的肌肉生长的理解目前仅限于由 类型2的肌肉纤维。新出现的证据表明，这些发现可能不会延伸到1型(慢抽搐)。 纤维。AS 1型纤维约占人类骨骼肌的50%，已知对 生理功能和健康，确定卫星细胞在1型纤维生长过程中的作用具有临床意义 重要性。 为了解决我们对肌肉生长调控的理解中的这些关键差距， 将使用PAX7-DTA小鼠品系，允许可诱导的卫星细胞枯竭，并有短和长 将采用长期负重车轮跑模型诱导足底肥大(100%型2)和 卫星细胞耗竭(SC-)和充盈(SC+)小鼠的比目鱼肌(50%1型和2型各50%)。这个设计 将使我能够确定(1)肌肉生长和生长过程中对卫星细胞的纤维类型特定要求 (2)阐明调控卫星细胞非依赖性和依赖性肌肉生长的细胞内机制。 经过一段时间的肌肉肥大。这项研究的结果将提供必要的信息 评估卫星细胞靶向治疗的潜力，并潜在地确定代偿性 能够在没有卫星细胞的情况下生长的机制，这些卫星细胞也可能成为潜在的治疗靶点。 此外，该项目的完成将为有前途的年轻人提供一个绝佳的培训机会。 科学家。

PROJECT SUMMARY/ABSTRACT Physical inactivity, advancing age, limb immobilization, degenerative diseases and various systemic diseases (many cancers, sepsis, HIV, COPD, kidney disease) all lead to skeletal muscle wasting. The loss of muscle mass is of major clinical importance because it leads to an increased risk for morbidity, disability, and the loss of independence; collectively contributing to a substantive increase in healthcare utilization and cost. A rapidly aging U.S population will undoubtedly lead to an increase in the prevalence of sarcopenia and the age- related systemic diseases that cause cachexia. In order to reduce concomitant increases in healthcare costs, developing interventional strategies that promote healthy aging and extend functional independence is critical. Gaining a fundamental understanding for the role of muscle stem cells (satellite cells) during muscle hypertrophy will increase the feasibility of targeting these cells and increasing their ability to promote muscle growth. Our lab previously showed that while a lack of satellite cells does not limit short-term muscle growth, satellite cells are required to support sustained growth, at least in type 2 (fast twitch) fibers. The compensatory pathways activated in the absence of satellite cell fusion to enable short-term muscle growth in type 2 fibers are of interest. In line with this, the mechanism precipitating a shift in the requirement for satellite cells during sustained muscle growth is unknown. Due to the method of overload used in previous studies, our understanding for satellite cell-mediated muscle growth is currently restricted to muscles comprised exclusively of type 2 muscle fibers. Emerging evidence suggests that these findings may not extend to type 1 (slow twitch) fibers. As type 1 fibers comprise ~50% of human skeletal muscle and are known to positively influence physical function and health, determining the role of satellite cells during type 1 fiber growth is of clinical importance. In order to address these critical gaps in our understanding of the regulation of muscle growth, the Pax7-DTA mouse strain will be used, allowing for the inducible depletion of satellite cells, and a short and long term weighted wheel running model will be used to induce hypertrophy in the plantaris (100% type 2) and the soleus (50% type 1 and 50% type 2) muscles in satellite cell deplete (SC-) and replete (SC+) mice. This design will allow me to determine (1) the fiber type-specific requirements for satellite cells during muscle growth and (2) elucidate the intracellular mechanisms regulating satellite cell independent and dependent muscle growth over a time course of muscle hypertrophy. The findings from this study will provide information necessary to evaluate the therapeutic potential of satellite cell targeted approaches, and potentially identify compensatory mechanisms enabling growth in the absence of satellite cells that may also be potential therapeutic targets. Moreover, the completion of this project will provide an outstanding training opportunity for a promising young scientist.