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: 10295407
• 负责人: JOHN Joseph MCCARTHY
• 金额: $ 35.71万
• 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/10295407
• 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.

项目概要 随着年龄的增长，骨骼肌质量的损失具有重要的临床意义，因为它与骨骼肌质量的增加有关。 发病率和死亡率以及生活质量显着恶化。还有一个加高的 对识别导致合成代谢缺乏的细胞和分子机制感兴趣 老化肌肉对肥大刺激的反应。使用卫星细胞治疗骨骼肌质量损失 鉴于干细胞的特性和在术后的重要作用，被认为是一种有前途的治疗策略。 出生时肌肉的生长和再生。我们的研究结果促使我们进行机械 分析卫星细胞的两种众所周知的功能；与肌纤维融合，为肌纤维提供额外的核 肥大性生长，对卫星细胞扩张的其他功能性后果的响应 各种外源刺激（例如运动），作为响应的卫星细胞丰度的增加 机械超负荷远远超过与肌纤维尺寸增加相关的肌核增生。我们报道了 通过调节卫星细胞，卫星细胞对于骨骼肌的最佳长期肥大生长是必要的。 细胞外基质。激活的卫星细胞通过细胞外囊泡抑制成纤维细胞胶原蛋白的产生 (EV) 递送 miR-206，揭示了卫星细胞以前未被识别的功能，此外还提供 卫星细胞与肌肉内其他细胞通讯的机制。我们现在有体内 来自 Pax7-tdT 报告小鼠的卫星细胞间通讯的单细胞 (sc)RNA-seq 证据 卫星细胞与 FAPs/纤维化细胞和内皮细胞进行通信的网络 肥大性生长。目标 1 将检验老化对该通信网络产生负面影响的假设 抑制细胞外基质的适当重塑，从而抑制肥大。我们还开发了 一种新型小鼠模型，使我们能够同时消耗卫星细胞并标记驻留肌核，Aim 2 将使用该模型和单肌核 (smn)RNA-seq 来表征年龄相关的变化 驻留肌核转录组并确定在缺失情况下实现短期肥大的机制 成年小鼠的卫星细胞在老年时会丢失。目标 3 将使用额外的新开发的报告基因 小鼠能够对卫星细胞核进行特异性和稳定的标记，以确定衰老如何改变 卫星细胞衍生的肌核转录组响应肥大刺激。我们假设在 老化的肌肉，卫星细胞衍生的肌核改变了转录输出，这不会促进 肥大反应，卫星细胞融合受损或有缺陷的卫星细胞可能会产生负面影响 影响常驻肌核转录活性，导致生长受损。定义融合依赖 -卫星细胞的独立作用和与年龄相关的变化对肌肉适应性产生负面影响 将确定潜在的新目标，以促进骨骼肌在缺乏活动、衰老过程中和在 面对肌肉萎缩疾病。