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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：
10660957
负责人：
Gretchen A Meyer
金额：
$ 34.5万
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/10660957
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 Cell secretion 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 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 Regenerative response Rehabilitation therapy Research Resistance Role Rotator Cuff Schedule Signal Transduction Sorting 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和身体残疾降低了数百万美国人的生活质量。这些身体限制与肌间/肌内脂肪组织 (IMAT) 的病理性积累有关涉及众多人群和疾病。这种联系与 IMAT 积累的阻力相结合标准饮食和运动重塑线索表明 IMAT 是一个持久且未解决的临床问题问题，可能会阻碍维持或增加肌肉力量的康复努力。长期目标这项研究的目的是利用我们对脂肪-肌肉交互作用的理解来治疗调节 IMAT 旁分泌信号促进肌肉生长和再生。最近，IMAT 被确定为一种特殊的脂肪亚型，称为米色脂肪，可以刺激它采用棕色脂肪的特征，潜在地包括促再生因子的分泌。本提案的主要目标是确定棕色脂肪对肌肉的促再生作用机制以及 IMAT 是否可以模仿该作用刺激。我们的中心假设是棕色脂肪通过增强生肌来促进肌肉再生通过旁分泌分泌的卵泡抑素进行分化。为了解决我们的假设，我们的方法将使用我们的小说小鼠肌间脂肪移植系统，用于模拟旁分泌脂肪-肌肉交互作用。我们将使用这个系统控制棕色脂肪信号传导的时间和组成，以探索细胞反应的机制肌肉再生期间（目标 1）以及卵泡抑素在介导该反应中的作用（目标 2）。我们还将通过刺激小鼠和人类探索模仿棕色脂肪旁分泌信号传导的治疗潜力 IMAT（目标 3）。总而言之，这些研究将拓宽我们对棕色脂肪信号传导基本生物学的理解， IMAT 肌肉串扰的性质以及刺激 IMAT 和其他米色库的治疗潜力脂肪以改善组织生理机能。