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

项目总结/摘要 缺乏体力活动、年老、肢体不能活动、退行性疾病和各种全身性疾病 疾病（许多癌症、败血症、HIV、COPD、肾病）都导致骨骼肌消耗。的损失 肌肉质量是主要的临床重要性，因为它导致发病率，残疾， 独立性的丧失;共同导致医疗保健利用率和成本的大幅增加。一 快速老龄化的美国人口无疑将导致肌肉减少症的患病率增加， 引起恶病质的相关系统性疾病。为了减少随之而来的医疗保健费用的增加， 制定促进健康老龄化和扩大功能独立性的干预战略至关重要。 获得对肌肉干细胞（卫星细胞）在肌肉生长过程中的作用的基本了解 肥大将增加靶向这些细胞的可行性，并增加它们促进肌肉生长的能力。 增长我们的实验室先前表明，虽然缺乏卫星细胞不会限制短期肌肉生长， 至少在2型（快速收缩）纤维中，需要卫星细胞来支持持续的生长。补偿 在没有卫星细胞融合的情况下激活的途径，使2型纤维的短期肌肉生长成为可能 很有意思与此相一致的是， 持续的肌肉生长是未知的。由于在以前的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 2型肌纤维新出现的证据表明，这些发现可能不会扩展到1型（慢颤） 纤维由于1型纤维占人体骨骼肌的约50%，并且已知对人体骨骼肌的生长有积极影响， 身体功能和健康，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节的理解中的这些关键差距， 将使用Pax 7-DTA小鼠品系，允许卫星细胞的诱导性耗竭，并且将使用短和长的细胞周期。 长期加权轮跑模型将用于诱导跖肌肥大（100% 2型）， 比目鱼肌（50%1型和50%2型）肌肉中的卫星细胞耗尽（SC-）和充满（SC+）小鼠。这种设计 将允许我确定（1）在肌肉生长期间卫星细胞的纤维类型特定要求， (2)阐明卫星细胞非依赖性和依赖性肌肉生长的细胞内调节机制 随着时间的推移肌肉肥大。这项研究的结果将提供必要的信息， 评估卫星细胞靶向方法的治疗潜力，并潜在地确定代偿性 在缺乏卫星细胞的情况下能够生长的机制也可能是潜在的治疗靶点。 此外，该项目的完成将为有前途的年轻人提供一个出色的培训机会。 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.