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

确定骨骼肌肥大期间卫星细胞的纤维类型特定要求

• 批准号: 9907005
• 负责人: Davis A. Englund
• 金额: $ 1.69万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-24 至 2020-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907005
• 关键词: Address; Adult; Aging; Cachexia; Cell Nucleus; Cell fusion; Cells; Chemistry; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Data; Degenerative Disorder; Development; Dissociation; Elderly; Expression Profiling; Fast-Twitch Muscle Fibers; Fiber; Future; Gene Expression; Genetic Transcription; Goals; Growth; HIV; Health; Health Care Costs; Human; Hypertrophy; Immobilization; Intervention; Kidney Diseases; Knowledge; Label; Lead; Limb structure; Malignant Neoplasms; Mechanics; Mediating; Metabolic; Metabolism; Methods; Modeling; Molecular and Cellular Biology; Morbidity - disease rate; Mouse Strains; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Output; Pathway interactions; Personal Satisfaction; Phase; Physical Function; Plantaris muscle; Population; Prevalence; RNA; Regulation; Research; Risk; Role; Running; Scientist; Sepsis; Skeletal Muscle; Soleus Muscle; Stimulus; Systemic disease; Tamoxifen; Techniques; Testing; Therapeutic; Time; Training; Transcriptional Regulation; Transgenic Mice; Uridine; Wild Type Mouse; Work; age related; base; bench to bedside; design; disability; functional independence; genome-wide; health care service utilization; healthy aging; improved; interest; mouse model; muscle form; muscle hypertrophy; novel; physical conditioning; physical inactivity; response; restoration; sarcopenia; satellite cell; skeletal muscle wasting; skills; targeted treatment; therapeutic target; training opportunity; transcriptome sequencing; translational scientist; treatment strategy

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.

项目摘要/摘要 身体上的不活动，增长年龄，肢体固定，退化性疾病和各种系统性 疾病（许多癌症，败血症，HIV，COPD，肾脏疾病）都会导致骨骼肌浪费。损失 肌肉质量具有重要的临床重要性，因为它导致发病率，残疾和 失去独立性；共同促进医疗保健利用和成本的实质性增加。一个 迅速衰老的美国人口无疑会导致肌肉减少症的患病率和年龄增长。 引起恶病质的相关全身性疾病。为了减少医疗保健成本的同时增加， 制定促进健康衰老并扩展功能独立性的介入策略至关重要。 对肌肉过程中肌肉干细胞（卫星细胞）的作用有基本的了解 肥大将增加靶向这些细胞的可行性并增加促进肌肉的能力 生长。我们的实验室先前表明，尽管缺乏卫星细胞并不限制短期肌肉的生长，但 至少在2型（快速抽搐）纤维中，需要卫星细胞支持持续生长。补偿性 在没有卫星细胞融合的情况下激活的途径可以使2型纤维的短期肌肉生长 很感兴趣。与此相一致，在此期间，机制促成了卫星细胞需求的转移 持续的肌肉生长尚不清楚。由于先前研究中使用的超负荷方法，我们 目前，了解卫星细胞介导的肌肉生长的理解仅限于仅组成的肌肉 2型肌肉纤维。新兴证据表明，这些发现可能不会扩展到1型（缓慢的抽搐） 纤维。作为1型纤维占人类骨骼肌的50％，已知会积极影响 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是临床 重要性。 为了解决我们对肌肉生长调节的理解， 将使用PAX7-DTA小鼠应变，允许卫星细胞的诱导耗尽，并且短而长 术语加权车轮运行模型将用于诱导plantaris（100％类型）和 卫星细胞耗尽（SC-）和毛细血管（SC+）小鼠中的比目鱼（1型1型和50％2型2型）肌肉。这个设计 我将允许我确定（1）在肌肉生长过程中对卫星细胞的纤维类型特异性要求和 （2）阐明调节卫星细胞独立和依赖肌肉生长的细胞内机制 在肌肉肥大的时间内。这项研究的发现将为您提供必要的信息 评估卫星细胞靶向方法的治疗潜力，并有可能识别补偿性 在没有卫星细胞的情况下，机制也可以成为潜在的治疗靶标。 此外，该项目的完成将为一个有前途的年轻人提供出色的培训机会 科学家。