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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：
9895295
负责人：
Michael Kyba
金额：
$ 51.9万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895295
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 Regulation Research Role Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Skeletal Muscle Stem cells Testing Testosterone Therapeutic Therapeutic Intervention Tissues Woman age related aged aging population clinically relevant design estrogenic experimental study female sex hormone functional outcomes hormone deficiency in vivo injured insight male male sex hormones men muscle aging muscle regeneration receptor regenerative satellite cell self-renewal sex 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.

骨骼肌在一生中会反复受伤，需要不断再生。这骨骼肌的再生能力随着年龄的增长而显着下降，尽管具体的人们对导致这种下降的因素知之甚少。下降的一个关键系统性因素与女性年龄相关的是性激素雌二醇（E2）。我们实验发现操纵 E2 水平及其受体 ERα 的水平，特别是在年轻卫星细胞中成年女性会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在女性，探讨这种调节的性别特异性，并调查对老年人的干预措施老鼠。我们将阐明雌二醇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。在我们强劲的初步推动下数据，我们将检验 E2 是主要性激素调节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，我们设计实验来探究细胞生理学卫星细胞中 E2-ERα 信号轴的后果。目标 2 关注雌激素调节男性卫星细胞和肌肉再生的机制，测试刺激性假设 E2 在男性和女性中都发挥着重要作用。在目标 3 中，我们将询问老年小鼠卫星细胞对 E2 和新的第三代卫星细胞的反应选择性雌激素受体调节剂巴多昔芬 (BZA)，我们已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，我们利用状态最先进的转录和染色质分析方法，可深入了解信号传导例如，雌性和雌性卫星细胞之间的途径相似（或不同）当性激素或受体受到操纵时，男性。在这个项目完成后我们将了解 E2 如何通过以下方式促进整体骨骼肌健康的分子细节激素受体介导的机制，特别是在卫星细胞中。女性花费三分之一他们的生命处于 E2 缺乏状态和雄激素（因此潜在的雌激素作用介导）芳香酶）在男性中随着年龄的增长而下降。随着人口老龄化的不断加剧这种生物变量对骨骼肌的影响变得越来越重要健康被理解。