The role of satellite cells in skeletal muscle hypertrophy with aging

卫星细胞在衰老过程中骨骼肌肥大中的作用

• 批准号: 10468197
• 负责人: JOHN Joseph MCCARTHY
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468197
• 关键词: Ablation; Adult; Affect; Age; Aging; Cell Communication; Cell Nucleus; Cell fusion; Cells; Characteristics; Chronic; Clinical; Collagen; Communication; Deterioration; Doxycycline; Elderly; Endothelial Cells; Exercise; Extracellular Matrix; Female; Fibroblasts; Fibrosis; Foundations; Gene Expression; Genes; Genetic Transcription; Grant; Growth; Human; Hypertrophy; Immunohistochemistry; Impairment; In Vitro; Label; Mechanics; Messenger RNA; MicroRNAs; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Mus; Muscle; Muscle satellite cell; Muscular Atrophy; Natural regeneration; Output; Phenocopy; Plantaris muscle; Population; Population Dynamics; Process; Production; Quality of life; Reporter; Reporting; Rodent; Role; Skeletal Muscle; Stimulus; Systemic disease; Tamoxifen; Testing; Therapeutic; Therapeutic Uses; Time; Transcript; Wasting Syndrome; age related; aged; base; cell age; extracellular vesicles; human old age (65+); in vivo; intercellular communication; interest; male; mortality; mouse model; muscle aging; muscle form; muscle hypertrophy; novel; patient population; physical inactivity; prevent; progenitor; response; sarcopenia; satellite cell; single-cell RNA sequencing; skeletal muscle growth; skeletal muscle wasting; stem cells; transcriptome; transcriptome sequencing; young adult

Project Summary The loss of skeletal muscle mass with age is of clinical importance because it is associated with increased morbidity and mortality, as well as a marked deterioration in the quality of life. There is also a heightened interest in the identification of cellular and molecular mechanisms responsible for the lack of an anabolic response of aged muscle to hypertrophic stimuli. The use of satellite cells to treat loss of skeletal muscle mass is considered a promising therapeutic strategy given their stem cell characteristics and essential role in post- natal muscle growth and regeneration. The results of our studies have prompted us to perform mechanistic analyses of both of the well-known function of satellite cells; fusion to myofibers to provide additional nuclei for hypertrophic growth, to other functional consequences of satellite cell expansion that occurs in response to various exogenous stimuli such as exercise, as the increase in satellite cell abundance in response to mechanical overload far exceeds myonuclear accretion associated with increased myofiber size. We reported satellite cells were necessary for optimal long-term hypertrophic growth of skeletal muscle by regulating the extracellular matrix. Activated satellite cells repressed fibroblast collagen production via extracellular vesicle (EV) delivery of miR-206, revealing a previously unrecognized function of satellite cells, in addition to providing a mechanism through which satellite cells communicate with other cells within muscle. We now have in vivo single-cell (sc)RNA-seq evidence from Pax7-tdT reporter mice of a satellite cell intercellular communication network in which satellite cells communicate with FAPs/fibrogenic cells and endothelial cells during hypertrophic growth. Aim 1 will test the hypothesis that aging negatively impacts this communication network inhibiting proper remodeling of the extracellular matrix thereby inhibiting hypertrophy. We have also developed a novel mouse model that allows us to simultaneously deplete satellite cells and label resident myonuclei, Aim 2 will use this model and single-myonuclear (smn)RNA-seq to characterize age-dependent changes in the resident myonuclear transcriptome and identify mechanisms that enable short term hypertrophy in the absence of satellite cells in adult mice, which is lost in old age. Aim 3 will use an additional newly developed reporter mouse that enables specific and stable labeling of satellite cell nuclei to determine how aging alters the satellite cell-derived myonuclear transcriptome in response to a hypertrophic stimulus. We hypothesize that in aged muscle, satellite cell-derived myonuclei have altered transcriptional output that does not promote a hypertrophic response, and that impaired fusion of satellite cells or defective satellite cells may negatively impact resident myonuclear transcriptional activity contributing to impaired growth. Defining fusion-dependent and -independent roles of satellite cells and age-associated changes that negatively impact muscle adaptability will identify potential new targets to promote skeletal muscle growth in the face of inactivity, during aging and in the face of muscle wasting diseases.

项目摘要 随着年龄的增长，骨骼肌质量的丧失是临床重要性的，因为它与增加有关 发病率和死亡率，以及生活质量的明显恶化。也有一个增长 对鉴定导致缺乏合成代谢的细胞和分子机制的识别的兴趣 老年肌肉对肥厚刺激的反应。使用卫星细胞治疗骨骼肌质量的损失 鉴于其干细胞特征和在后期的重要作用，被认为是一种有希望的治疗策略 出生的肌肉生长和再生。我们的研究结果促使我们执行机械 卫星细胞的两个众所周知功能的分析；融合到肌纤维以提供额外的核 肥厚性生长，卫星细胞扩张的其他功能后果，这是为了响应于 各种外源刺激（例如运动），因为 机械超负荷远远超过了与肌纤维大小增加有关的肌核积聚。我们报道 通过调节 细胞外基质。活化的卫星细胞通过细胞外囊泡抑制了成纤维细胞胶原蛋白 （EV）MiR-206的传递，除了提供卫星细胞的先前未识别的功能，此外还提供了 卫星细胞与肌肉中其他细胞通信的机制。我们现在有体内 来自卫星细胞间通信的PAX7-TDT报道小鼠的单细胞（SC）RNA-seq证据 网络中，卫星细胞与FAP/纤维基细胞和内皮细胞进行通信 肥厚的生长。 AIM 1将检验以下假设，即衰老会对该通信网络产生负面影响 抑制细胞外基质的正确重塑，从而抑制肥大。我们也发展了 一种新型的鼠标模型，使我们能够同时耗尽卫星细胞并标记居民肌核心，AIM 2将使用此模型和单甲核（SMN）RNA-Seq来表征年龄依赖性的变化 居民肌核转录组并确定在没有的情况下能够使短期肥大的机制 成年小鼠中的卫星细胞，该细胞在老年时丢失。 AIM 3将使用其他新开发的记者 使卫星细胞核特定稳定标记的小鼠可以确定衰老如何改变 卫星细胞衍生的肌核转录组响应肥厚刺激。我们假设在 年龄的肌肉，卫星细胞衍生的肌核的转录输出改变了，但不会促进 肥厚的反应，卫星细胞或缺陷卫星细胞的融合受损可能会负面 影响常驻的肌核转录活性导致增长受损。定义融合依赖性 卫星细胞和与年龄相关的变化对肌肉适应性产生负面影响的无关角色 将确定潜在的新目标，以促进面对不活动，衰老和在内的骨骼肌生长 肌肉浪费疾病的表面。