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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

基本信息

批准号：
10634732
负责人：
Michael Kyba
金额：
$ 48.67万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634732
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 Estrogen deficiency Experimental Designs 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 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 estrogenic female sex hormone functional outcomes hormone deficiency human old age (65+)in vivo injured insight male male sex hormones men muscle aging muscle regeneration pharmacologic receptor regeneration potential regenerative satellite cell self-renewal sex stem cells young adult

项目摘要

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.

骨骼肌在一生中不断受到损伤，需要不断地再生。这个骨骼肌再生的能力随着年龄的增长而显著下降，尽管特定的人们对控制这种下降的因素知之甚少。下降的一个关键系统性因素随着年龄的增长，女性体内的性激素是雌二醇(E2)。我们已经发现，实验性的幼年卫星细胞中雌二醇水平及其受体ERα的特异性调控成年雌性会导致卫星细胞池的大小减少和再生潜力的下降。这个项目试图了解这些影响的中介机制。女性，探索这一规定的性别特异性，并调查老年人的干预老鼠。我们将阐明雌激素和雌激素介导的分子和细胞再生细节。重要的是，肌肉收缩的功能结果。由我们强劲的初步调查推动数据，我们将检验E2是主要性激素调节的首要假设雌激素受体介导的骨骼肌维持机制卫星细胞。在目标1中，我们设计了探索细胞生理的实验。 E2-ERα信号轴在卫星细胞中的后果。目标2侧重于雌激素调节雄性卫星细胞和肌肉再生的机制，测试挑衅性认为雌二醇对男性和女性都有重要作用的假说。在《目标3》中，我们将老年小鼠卫星细胞对雌二醇和新的第三代的反应性选择性雌激素受体调节剂Bazedoxifene(BZA)，我们已经证明它是一种卫星细胞中的雌激素受体激动剂。在三个主要目标中的每一个中，我们都利用国家 ART转录和染色质分析方法，以深入了解信号例如，雌性和雌性卫星细胞之间相似(或不同)的通路当性激素或受体被操纵时，雄性。在这个项目完成后，我们将详细了解E2如何通过以下途径促进骨骼肌健康激素受体介导的机制--特别是在卫星细胞中。女性花费三分之一的时间处于E2缺乏状态和雄激素(从而介导潜在的雌激素效应)的生命芳香酶)在男性中随着年龄的增长而下降。随着老龄化人口的持续增加，这种生物变量对骨骼肌的影响变得越来越重要健康是可以理解的。