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Regulation of Skeletal Muscle Regeneration During Aging by Growth Differentiation Factor 11

生长分化因子 11 对衰老过程中骨骼肌再生的调节

基本信息

批准号：
9264456
负责人：
Jill Marie Goldstein
金额：
$ 1.28万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264456
关键词：
Adult Age Aging Animals Biological Assay Blood Blood Circulation Cell Count Cell physiology Cells Data Defect Development Drops Effectiveness Elderly Exhibits Flow Cytometry Fluorescence Microscopy Functional disorder GDF11 gene Gene Transfer Techniques Genetic Goals Growth and Development function Health Homeostasis Hormonal Impairment Injury Intervention Knock-in Knock-out Lead Life Locomotion Maintenance Mouse Strains Movement Mus Muscle Muscle Fibers Muscle function Muscle satellite cell Muscular Atrophy Natural regeneration Parabiosis Pathology Physiological Physiology Population Process Production Proliferating Proteins Quality of life RNA Interference Regenerative Medicine Regulation Reporter Role Skeletal Muscle Source Spleen Supplementation System Testing Therapeutic Tissues Work Youth age related age-related muscle loss aged base cell type experimental study improved functioning in vivo innovation insight interest juvenile animal knock-down loss of function mouse model muscle aging muscle regeneration novel novel therapeutic intervention novel therapeutics older patient premature prevent public health relevance recombinase-mediated cassette exchange reduced muscle mass regenerative repaired response response to injury satellite cell skeletal tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle is a highly organized tissue that functions to support bodily movement and locomotion. Throughout adult life, skeletal muscle undergoes a robust process of tissue regeneration in response to injury, yet the effectiveness of this process declines significantly during old age. This age-related skeletal muscle dysfunction poses a significant health concern for the elderly population, such that insufficient muscle repair can lead to decreased muscle mass, loss of strength and impaired quality of life. Thus, the development of novel therapeutics to prevent, delay or reverse age-associated skeletal muscle maladies is of significant biomedical interest. The overarching goal of this proposal is to investigate a recently identified systemic regulator of skeletal muscle health, Growth Differentiation Factor 11 (GDF11). While circulating levels of GDF11 are abundant during youth, GDF11 levels decline substantially with age due to unknown mechanisms. Extensive preliminary data indicate that restoring youthful levels of GDF11 to aged mice substantially improves the function of skeletal muscle stem cells (satellite cells) and enhances the physiology and repair potential of aged muscle. Based on these findings, I propose to test the hypothesis that decreasing systemic GDF11 levels during aging contributes directly to age-related defects in skeletal muscle function. To gain insight into the mechanisms responsible for the loss of GDF11 from circulation during aging, I will (1) define the discrete cell types that produce systemic GDF11 and evaluate changes in their number and GDF11 expression level during aging. Preliminary findings implicate the spleen as a candidate source of systemic GDF11 expression, as splenic expression of GDF11 is abundant during youth and exhibits an age-dependent decline. A knock-in GDF11 reporter mouse strain will be harnessed to identify GDF11-expressing cell types in the spleen by fluorescence microscopy and flow cytometry and evaluate these findings in the context of age-related decreases in GDF11 expression. Additionally, the proposed studies will (2) determine the function of circulating GDF11 in regulating skeletal muscle homeostasis and repair potential during youth. Two inducible loss of function approaches will be used to deplete GDF11 during youth and assay the resulting effects on satellite cell function, skeletal muscle homeostasis and repair potential in vivo. Altogether, these studies will provide mechanistic insights into the regulation of systemic GDF11 during aging and illuminate the role of GDF11 as a hormonal regulator of youthful skeletal muscle function.