Role of skeletal muscle stem cell fusion and fibrosis during aging

骨骼肌干细胞融合和纤维化在衰老过程中的作用

基本信息

批准号：
10375373
负责人：
Douglas Paul Millay
金额：
$ 34.98万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375373
关键词：
Ablation Adult Age Aging Cell Count Cell fusion Cells Characteristics Chimeric Proteins Chronic Chronic Disease Consequentialism Data Defect Development Diphtheria Disabled Persons Elderly Environment Evaluation Exercise Exhibits Extracellular Matrix Fibroblasts Fibrosis Functional disorder Genetic Genetic Models Goals Growth Homeostasis Hypertrophy Impairment Incidence Injury Intramuscular Knowledge Lead Maintenance Modeling Molecular Mus Muscle Muscle function Muscle satellite cell Muscular Atrophy Natural regeneration Pathologic Physiological Prevalence Process Proliferating Proteins Reagent Research Role Skeletal Muscle Stimulus Testing Time Tissues Work age effect age related aged base combat genetic manipulation in vivo insight mouse model muscle aging muscle form novel novel strategies novel therapeutic intervention overexpression repaired resilience response sarcopenia sedentary skeletal muscle wasting

项目摘要

Project Summary/Abstract Sarcopenia is a devastating skeletal muscle condition that occurs in advanced age and due to various chronic conditions. Despite the widespread prevalence of sarcopenia there are no treatment options and the mechanisms underlying this process are not completely understood. Hallmark characteristics of skeletal muscle aging are a reduction in myofiber size and number, dysregulated muscle function, and an increased incidence of fibrosis. An additional process altered during aging is the activity of muscle stem cells (MuSCs), which typically are quiescent but in a young environment function to fully repair damaged muscle and allow muscle to adapt to external stimuli. Although MuSCs are clearly required for development and regeneration, we still do not understand their exact role during muscle homeostasis and aging. To this end, we have generated a unique mouse model that ablates MuSC fusion activity but maintains their presence within the tissue. Our recent studies showed that MuSC fusion is required for muscle growth in a young environment, and that without MuSC fusion, pronounced development of fibrosis ensues. Moreover, our preliminary data indicate that MuSC fusion is dysregulated in aged skeletal muscle. Thus, we hypothesize that fusion of MuSCs with myofibers is necessary to maintain myofiber integrity, and dysregulation of this process leads to pathological extracellular matrix (ECM) remodeling during aging. To definitively answer these questions, we have generated numerous novel genetic reagents to manipulate both MuSC fusion and fibrosis in vivo. Based on these preliminary data and unique mouse models we propose to comprehensively determine the role for MuSCs and evaluate the consequences of fibrosis development during skeletal muscle aging. Specifically, we propose to: 1) elucidate the requirement of MuSC fusion for muscle adaptation during aging 2) molecularly dissect the mechanisms of fusion in aged skeletal muscle and 3) define the relationship between fibrosis and MuSC fusion during the development of sarcopenia. Successful completion of these studies will provide unique insight into the general mechanisms of MuSC-dependent muscle aging and provide new knowledge that will identify new therapeutic strategies to combat sarcopenia.

项目摘要/摘要肌肉减少症是一种毁灭性的骨骼肌状况，发生在高龄，并且由于各种慢性状况。尽管肌肉减少症的普遍普遍存在，但没有治疗选择该过程的基础机制尚未完全理解。骨骼特征肌肉衰老是肌纤维的大小和数量减少，肌肉功能失调，增加纤维化的发生率。衰老过程中发生的另一个过程是肌肉干细胞（MUSC）的活性，通常是静止的，但在年轻的环境中可以完全修复受损的肌肉并允许肌肉适应外部刺激。尽管显然需要MUSC进行发展和再生，但我们仍然不了解它们在肌肉稳态和衰老中的确切作用。为此，我们有产生了一个独特的鼠标模型，该模型将MUSC融合活动烧蚀但保持其存在组织。我们最近的研究表明，在年轻环境中肌肉生长需要MUSC融合，在没有MUSC融合的情况下，随之而来的纤维化发生了明显的发展。而且，我们的初步数据表明MUSC融合在老年骨骼肌中失调。因此，我们假设具有肌纤维的MUSC对于保持肌纤维完整性是必要的，并且该过程的失调导致病理细胞外基质（ECM）在衰老过程中重塑。为了明确回答这些问题，我们已经产生了许多新型的遗传试剂，以操纵体内MUSC融合和纤维化。基于在这些初步数据和独特的鼠标模型上，我们建议全面确定 MUSC并评估骨骼肌老化期间纤维化发育的后果。具体来说，我们提议：1）阐明在衰老期间对MUSC融合对肌肉适应的需求2）分子剖析老年骨骼肌融合机制，3）定义纤维化与 MUSC融合在肌肉减少症的发展过程中。这些研究的成功完成将提供独特的深入了解MUSC依赖性肌肉衰老的一般机制，并提供新知识确定对抗肌肉减少症的新治疗策略。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Myomerger promotes fusion pore by elastic coupling between proximal membrane leaflets and hemifusion diaphragm.

DOI：
10.1038/s41467-020-20804-x
发表时间：
2021-01-21
期刊：
Nature communications
影响因子：
16.6
作者：
Golani G;Leikina E;Melikov K;Whitlock JM;Gamage DG;Luoma-Overstreet G;Millay DP;Kozlov MM;Chernomordik LV
通讯作者：
Chernomordik LV

Cell Fusion: Merging Membranes and Making Muscle.