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.

骨骼肌在一生中会反复受伤，需要不断再生。的 骨骼肌的再生能力随着年龄的增长而显著下降，尽管特定的 人们对这种下降的原因知之甚少。下降的一个关键系统性因素 与年龄相关的是女性的性激素，雌二醇（E2）。我们发现实验性的 在年轻的卫星细胞中特异性地操纵E2水平及其受体ERα 成年雌性导致卫星细胞池大小减少和再生潜力下降。 该项目旨在了解这些影响的介导机制， 女性，探讨这种调节的性别特异性，并调查干预老年人 小鼠我们将阐明雌二醇介导的分子和细胞再生的细节， 重要的是肌肉收缩的功能结果。在我们强大的初步 数据，我们将测试总体假设，即E2是主要的性激素调节 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，我们设计实验来探测细胞生理学 E2-ERα信号轴在卫星细胞中的作用。目标2关注雌激素 机制调节卫星细胞和肌肉再生的男性，测试挑衅 假设E2在男性和女性中起着重要作用。在目标3中， 老年小鼠卫星细胞对E2和第三代新卫星细胞询问反应性 选择性雌激素受体调节剂，bazedoxifene（BZA），我们已经证明是一种 雌激素受体激动剂的卫星细胞。在这三个主要目标中，我们利用国家 本领域的转录和染色质分析方法，以获得深入了解信号转导 例如，来自雌性的卫星细胞之间相似（或不同）的途径， 男性当性激素或受体被操纵。在这个项目完成后，我们 我将从分子水平上详细了解E2是如何通过以下途径促进骨骼肌健康的： 激素受体介导的机制，特别是在卫星细胞。女性花三分之一的时间 他们的生活在E2缺乏状态和雄激素（从而潜在的雌激素效应介导 随着年龄的增长，男性的芳香化酶水平下降。随着人口老龄化的不断加剧， 这一生物学变量对骨骼肌的影响变得越来越重要， 健康要理解。