Changes in myogenic progenitor potential with age

肌源性祖细胞潜能随年龄的变化

• 批准号: 7287420
• 负责人: CHARLOTTE A. PETERSON
• 金额: $ 27.41万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287420
• 关键词: Accounting; Adipocytes; Affect; Age; Aging; Area; Cells; Coculture Techniques; Collaborations; Data; Elderly; Equilibrium; Exercise; Gene Expression; Genes; Goals; Growth; Human; Hypertrophy; In Vitro; Injury; Intervention Studies; Knock-out; Ligands; Link; Lipids; Maintenance; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Myoblasts; Myofibroblast; Obesity; Prevention; Property; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; Transgenic Organisms; Translating; Treatment Protocols; Work; aged; design; frailty; in vitro Model; in vivo; novel; postnatal; progenitor; programs; repaired; response; size

DESCRIPTION (provided by applicant): This project will explore a novel mechanism potentially contributing both to muscle atrophy and increased muscle lipid with age. Our work shows that in the mouse, the progenitors present in muscle that are primarily responsible for postnatal muscle growth, repair, and maintenance, activate an adipocyte-like gene program with age. The balance between myogenic and adipogenic potential appears to be regulated by Wnt signaling. In fact, the constellation of Wnt ligands present and the signaling pathways activated appear to crosstalk to control muscle size and lipid content. Thus, Wnt signaling may provide the mechanistic link whereby exercise influences both muscle properties. We hypothesize that Wnt signaling is altered in myogenic progenitors as a function of age contributing to impaired muscle function through loss of muscle mass and increased intramyocellular lipid following injury. In addition, intermyocellular lipid increases with age and we will assess the cellular properties of myofibroblasts to test the hypothesis that changes in their potential through altered Wnt signaling may contribute to lipid accumulation surrounding myofibers. In Aim 1 we will identify the signaling pathways that account for the distinct function of WntlOb in repressing adipogenic gene expression compared to other Wnts that promote myogenic differentiation and hypertrophy, and determine the role of changes in Wnt signaling in altering myogenic progenitor potential with age. Myofibroblasts will be characterized in vitro in Aim 2 to determine if adipogenic potential increases with age, potentially contributing to intermyocellular lipid. Co-culture of myogenic progenitors and myofibroblasts from different aged mice will determine if age affects their interaction. In Aim 3, myogenic progenitors will be "exercised" in vitro with a Flexcell stretcher to attempt to alter adipogenic potential. Lipid accumulation and myotube size will be quantified to determine if the effects of exercise differ with age through altered signaling. Preliminary data in human myogenic progenitors suggest that age also increases their adipogenic potential and focused analyses will be translated into humans. In Aim 4, myogenic progenitors and myofibroblasts will be isolated from older compared to younger humans to characterize myogenic and adipogenic differentiation potential that will be correlated with age, muscle adiposity, size and strength. The effects of an exercise regimen on muscle properties in vivo will be assessed in relation to changes in myogenic progenitor potential in vitro. We will examine the underlying mechanisms involved, and whether response differs with age. The long term goal of this research is to characterize changes in cell fate with age and determine their contribution to impaired muscle function in the elderly. Using this information, rational new strategies for frailty prevention can be designed and tested.

描述（由申请人提供）：该项目将探索一种可能导致肌肉萎缩和肌肉脂质随着年龄增加而增加的新机制。我们的工作表明，在小鼠中，肌肉中存在的祖细胞主要负责出生后肌肉的生长、修复和维护，并随着年龄的增长激活脂肪细胞样基因程序。肌源性和脂肪性潜力之间的平衡似乎受到 Wnt 信号传导的调节。事实上，Wnt 配体群的存在和激活的信号通路似乎相互影响来控制肌肉大小和脂质含量。因此，Wnt 信号传导可能提供运动影响两种肌肉特性的机制联系。我们假设肌源性祖细胞中的 Wnt 信号传导随着年龄的增长而改变，通过肌肉质量的损失和损伤后肌细胞内脂质的增加导致肌肉功能受损。此外，肌细胞间脂质随着年龄的增长而增加，我们将评估肌成纤维细胞的细胞特性，以检验以下假设：通过改变 Wnt 信号传导而改变其潜力可能有助于肌纤维周围的脂质积累。在目标1中，我们将鉴定与促进肌原分化和肥大的其他Wnt相比，解释Wnt10b在抑制脂肪形成基因表达中的独特功能的信号传导途径，并确定Wnt信号传导的变化在随年龄改变肌原祖细胞潜力中的作用。目标 2 将在体外对肌成纤维细胞进行表征，以确定成脂潜力是否随着年龄的增长而增加，从而可能导致肌细胞间脂质的形成。来自不同年龄小鼠的肌源性祖细胞和肌成纤维细胞的共培养将确定年龄是否影响它们的相互作用。在目标 3 中，将使用 Flexcell 担架在体外“锻炼”肌源性祖细胞，以尝试改变脂肪形成潜力。脂质积累和肌管大小将被量化，以确定运动的效果是否因信号改变而随年龄而变化。人类肌源祖细胞的初步数据表明，年龄也增加了它们的脂肪形成潜力，重点分析将转化为人类。在目标 4 中，将从老年人和年轻人中分离出肌源祖细胞和肌成纤维细胞，以表征与年龄、肌肉肥胖、大小和力量相关的肌源和脂肪分化潜力。运动方案对体内肌肉特性的影响将根据体外肌原祖细胞潜力的变化进行评估。我们将研究所涉及的潜在机制，以及反应是否随年龄而变化。这项研究的长期目标是描述细胞命运随年龄变化的特征，并确定它们对老年人肌肉功能受损的影响。利用这些信息，可以设计和测试预防衰弱的合理新策略。