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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：
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
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/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

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伤，需要不断再生。的