Promoting Muscle Regeneration through Adipose Signaling

通过脂肪信号促进肌肉再生

基本信息

批准号：
10214535
负责人：
Gretchen A Meyer
金额：
$ 33.61万
依托单位：
WASHINGTON UNIVERSITY
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：
2019-07-22 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214535
关键词：
Address Adipocytes Adipose tissue Adjuvant Therapy Adopted American Animal Model Area Biological Assay Biological Models Biology Biopsy Brown Fat Cell Differentiation process Cell Respiration Cells Cellular Assay Chronic Chronic Care Clinical Contralateral Cues Culture Media Development Differentiation Antigens Digestion Direct Lytic Factors Disease Exhibits Fatty acid glycerol esters Fiber Follistatin Gel Genetic Transcription Growth Harvest Histologic Hormones Human Hydrogels Inflammatory Injectable Injections Injury Intramuscular Knock-out Knowledge Link Mediating Mediator of activation protein Modeling Morbidity - disease rate Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Myopathy Natural regeneration Nature Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Paracrine Communication Pathologic Pathology Pathway interactions Pharmaceutical Preparations Phenotype Physiology Population Production Proliferation Marker Property Quality of life Rehabilitation therapy Research Resistance Role Rotator Cuff Schedule Signal Transduction Source System Therapeutic Thinking Time Tissues Transplantation Up-Regulation Work adipokines autocrine diet and exercise experimental study improved in vivo muscle regeneration muscle strength nanocomposite novel novel therapeutics paracrine physically handicapped prevent progenitor regenerative rehabilitative care response rotator cuff tear sarcopenia satellite cell stem cells targeted treatment therapy development transcription factor transcriptome sequencing transplant model

项目摘要

PROJECT SUMMARY Persistent muscle weakness and physical disability decrease quality of life for millions of Americans. These physical limitations are linked with pathological accumulation of inter/intramuscular adipose tissue (IMAT) across numerous populations and morbidities. This link combined with the resistance of IMAT accumulation to standard diet and exercise remodeling cues points to IMAT as being a persistent and unaddressed clinical problem, likely impeding rehabilitative efforts to maintain or increase muscle strength. The long-term objective of this research is to leverage our understanding of fat-muscle cross-talk to therapeutically modulate IMAT paracrine signaling to promote muscle growth and regeneration. Recently, IMAT has been identified as a specialized sub-type of fat called beige fat, that can be stimulated to adopt features of brown fat, potentially including the secretion of pro-regenerative factors. It is the primary objective of this proposal to determine the mechanisms of pro-regenerative action of brown fat on muscle and whether this action can be mimicked by IMAT stimulation. Our central hypothesis is that brown fat promotes muscle regeneration by enhancing myogenic differentiation via paracrine secreted follistatin. To address our hypothesis, our approach will use our novel system of mouse intermuscular fat transplant to model paracrine fat-muscle cross-talk. We will use this system to control the timing and composition of brown fat signaling for mechanistic exploration of the cellular response during muscle regeneration (aim 1) and the role of follistatin in mediating that response (aim 2). We will also explore the therapeutic potential of mimicking brown fat paracrine signaling via stimulation in mouse and human IMAT (aim 3). Altogether, these studies will broaden our understanding of the basic biology of brown fat signaling, the nature of IMAT-muscle cross-talk and the therapeutic potential for stimulating IMAT and other depots of beige fat to improve tissue physiology.

项目摘要持续的肌肉无力贫困降低了数百万美国人的生活质量。 thysical的局限性与肌间脂肪组织（IMAT）的病理积累有关在众多的流行和病态中。标准饮食和锻炼改建线索指出，IMAT是持续且未解决的临床问题，可能阻碍了维持或增加肌肉力量的康复努力这项研究的是利用我们对脂肪肌肉串扰的理解，以调节IMAT 旁分泌信号转导促进肌肉的生长和再生。脂肪的专门亚型称为米色脂肪，可以刺激以采用棕色脂肪的特征，可能包括促进因素的分泌。棕色脂肪对肌肉的促进活性作用的机制以及是否可以通过IMAT模仿这种作用刺激我们的中心假设是棕色脂肪通过增强肌源通过旁分泌分泌的follistatin的区分。小鼠间的肌肉间脂肪跨弹药到模型旁分泌脂肪交叉词。控制棕色脂肪信号传导的时间和组成，以探索细胞反应在肌肉再生过程中（AIM 1）和Follistatin在介导该反应中的作用（AIM 2）探索通过小鼠和人类刺激模仿棕色脂肪旁分泌信号传导的治疗潜力 IMAT（目标3）。 IMAT肌肉串扰的性质和刺激IMAT其他米色库的治疗潜力脂肪以改善组织生理学。