Dissecting Effects of Estrogen Deficiency on Satellite Cells and Muscle Regeneration in Females and Males

剖析雌激素缺乏对女性和男性卫星细胞和肌肉再生的影响

• 批准号: 10417168
• 负责人: Michael Kyba
• 金额: $ 49.49万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417168
• 关键词: Age; Aging; Agonist; Androgens; Apoptosis; Aromatase; Biological; Biology; Cell Count; Cell physiology; Chromatin; Data; Dose; Environment; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Face; Female; Fiber; Gene Expression Profiling; Generations; Genetic Transcription; Gonadal Steroid Hormones; Health; Hormone Receptor; Impairment; Intervention; Knowledge; Life; Maintenance; Mediating; Molecular; Movement; Mus; Muscle; Muscle Contraction; Muscle function; Muscle satellite cell; Mutagenesis; Natural regeneration; Nature; Operative Surgical Procedures; Output; Pathway interactions; Pharmacology; Physiological; Play; Population; Proliferating; Quality of life; Regenerative capacity; Regulation; Research; Role; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Tissues; Woman; age related; aged; aging population; cell regeneration; clinically relevant; design; estrogenic; experimental study; female sex hormone; functional outcomes; hormone deficiency; human old age (65+); in vivo; injured; insight; male; male sex hormones; men; muscle aging; muscle regeneration; receptor; regeneration potential; regenerative; satellite cell; self-renewal; sex; stem cells; young adult

Skeletal muscle is repetitively injured throughout life and requires continual regeneration. The ability of skeletal muscle to regenerate declines significantly with age, although the specific factors that govern this decline are poorly understood. One key systemic factor that declines with age in females is the sex hormone, estradiol (E2). We have discovered that experimental manipulation of both E2 levels and that of its receptor ERα specifically in satellite cells of young adult females leads to decrement in satellite cell pool size and decline in regenerative potential. This project seeks to understand the mechanisms by which these effects are mediated in females, probes the sex-specific nature of this regulation, and investigates interventions in aged mice. We will elucidate the molecular and cellular regenerative details mediated by estradiol and importantly the functional outcomes on muscle contraction. Driven by our robust preliminary data, we will test the overarching hypothesis that E2 is the primary sex hormone regulating skeletal muscle maintenance through estrogen receptor-mediated mechanisms in satellite cells. In Aim 1 we design experiments to probe the cellular physiological consequences of the E2-ERα signaling axis in satellite cells. Aim 2 focuses on estrogenic mechanisms regulating satellite cells and muscle regeneration of males, testing the provocative hypothesis that E2 plays a significant role in males as well as females. In Aim 3 we will interrogate responsiveness of satellite cells in aged mice to E2 and a new, third generation selective estrogen receptor modulator, bazedoxifene (BZA), which we have shown to be an estrogen receptor agonist in satellite cells. Within each of the three primary aims we utilize state of the art transcriptional and chromatin profiling approaches to gain insight into signaling pathways, for example, that are similar (or distinct) between satellite cells from females and males when sex hormones or receptors are manipulated. At the completion of this project we will know in molecular detail how E2 contributes to overall skeletal muscle health through hormone receptor mediated-mechanisms specifically in satellite cells. Women spend one-third of their life in an E2-deficient state and androgen (and thus potential estrogenic effects mediated by aromatase) declines in males with age. As the aging population continues to increase it becomes increasingly important that the impact of this biological variable on skeletal muscle health be understood.

骨骼肌在一生中重复受伤，需要连续再生。这 骨骼肌的再生能力随着年龄的增长而显着下降，尽管 控制这种下降的因素知之甚少。下降的一个关键系统因素 女性年龄是性激素，雌二醇（E2）。我们发现了实验 操纵两个E2水平及其受体ERα的水平，专门在年轻的卫星细胞中操纵 成年女性导致卫星细胞池大小的减小和再生潜力下降。 该项目旨在了解这些效果在 女性，问题是该法规的性别特定性质，并研究了老年人的干预措施 老鼠。我们将阐明雌二醇和细胞再生细节由雌二醇和 重要的是，肌肉收缩的功能结果。由我们强大的初步驱动 数据，我们将测试E2是主要的性骑士法规的总体假设 通过雌激素受体介导的机制维持骨骼肌 卫星细胞。在目标1中，我们设计实验以探测细胞生理 卫星细胞中E2-ERα信号轴的后果。 AIM 2专注于雌激素 调节卫星细胞和雄性肌肉再生的机制，测试了挑衅性 假设E2在男性和女性中起着重要作用。在目标3中，我们将 询问老年小鼠对E2的卫星细胞的响应性和新的第三代 选择性雌激素受体调节剂Bazedoxifene（BZA），我们已证明是一个 卫星细胞中的雌激素受体激动剂。在我们利用状态的三个主要目标中的每一个中 艺术转录和染色质分析方法，以洞悉信号传导 例如，途径在女性的卫星细胞之间相似（或不同） 男性在操纵性恐怖或接收者时。该项目完成时，我们 将通过分子详细了解E2如何通过 马酮受体介导的机制专门在卫星细胞中。妇女花费三分之一 它们在E2缺陷状态和雄激素中的生命（因此介导的潜在雌激素作用 通过芳香化酶的年龄下降。随着老龄化的人口继续增加 该生物变量对骨骼肌的影响变得越来越重要 健康可以理解。