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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.

项目总结/摘要肌肉减少症是一种毁灭性的骨骼肌状况，发生在老年人和由于各种慢性条件尽管肌肉减少症广泛流行，但没有治疗选择，这一过程的基本机制尚未完全了解。骨骼特征肌肉老化是肌纤维大小和数量减少，肌肉功能失调，纤维化的发病率。在衰老过程中改变的另一个过程是肌肉干细胞（MuSC）的活性，其通常是静止的，但在年轻的环境中起作用，以完全修复受损的肌肉，肌肉适应外界刺激。虽然MuSC显然是发育和再生所必需的，我们仍然不了解它们在肌肉稳态和衰老过程中的确切作用。为此我们产生了一种独特的小鼠模型，该模型消除了MuSC融合活性，但保持了它们在细胞内的存在。组织.我们最近的研究表明，MuSC融合是年轻环境中肌肉生长所必需的，而没有MuSC融合，则纤维化增强的显著发展。此外，我们的初步数据表明MuSC融合在老化骨骼肌中失调。因此，我们假设，具有肌纤维的MuSC是维持肌纤维完整性所必需的，并且该过程的失调导致衰老过程中病理性细胞外基质（ECM）重塑。为了明确回答这些问题，我们已经产生了许多新的遗传试剂来操纵体内MuSC融合和纤维化。基于根据这些初步数据和独特的小鼠模型，我们建议全面确定 MuSC和评估骨骼肌老化过程中纤维化发展的后果。我们特别拟：1）阐明MuSC融合对衰老过程中肌肉适应的要求2）分子水平分析老年骨骼肌融合的机制; 3）明确纤维化与骨骼肌纤维化之间的关系。肌肉减少症发展过程中的MuSC融合。成功完成这些研究将提供独特的深入了解MuSC依赖性肌肉衰老的一般机制，并提供新的知识，确定新的治疗策略来对抗肌肉减少症。

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.

DOI：
10.1016/j.tcb.2019.09.002
发表时间：
2019-12
期刊：
Trends in cell biology
影响因子：
19
作者：
Petrany MJ;Millay DP
通讯作者：
Millay DP

Skeletal muscle fibers count on nuclear numbers for growth.

骨骼肌纤维的生长依赖于核数量。

DOI：
10.1016/j.semcdb.2021.04.015
发表时间：
2021-11
期刊：
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
影响因子：
7.3
作者：
Prasad, Vikram;Millay, Douglas P.
通讯作者：
Millay, Douglas P.

Myonuclear content regulates cell size with similar scaling properties in mice and humans.

DOI：
10.1038/s41467-020-20057-8
发表时间：
2020-12-08
期刊：
Nature communications
影响因子：
16.6
作者：
Hansson KA;Eftestøl E;Bruusgaard JC;Juvkam I;Cramer AW;Malthe-Sørenssen A;Millay DP;Gundersen K
通讯作者：
Gundersen K

Nuclear numbers in syncytial muscle fibers promote size but limit the development of larger myonuclear domains.

DOI：
10.1038/s41467-020-20058-7
发表时间：
2020-12-08
期刊：
Nature communications
影响因子：
16.6
作者：
Cramer AAW;Prasad V;Eftestøl E;Song T;Hansson KA;Dugdale HF;Sadayappan S;Ochala J;Gundersen K;Millay DP
通讯作者：
Millay DP