Stem Cell Dysfunction in Aged Skeletal Muscle

老年骨骼肌干细胞功能障碍

基本信息

批准号：
10736449
负责人：
Albert Ernesto Almada
金额：
$ 57.49万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736449
关键词：
ADP Ribose Transferases ADP ribosylation Address Adenosine Diphosphate Ribose Adult Affect Age Aging Automobile Driving Biology of Aging Cell Cycle Cell surface Clinic Consumption Data Deterioration Elderly Enzymes Event Exercise Functional disorder Gene Activation Gene Targeting Genes Genetic Health Hour Immunohistochemistry Injury Knockout Mice Laboratories LacZ Genes Left Mass Spectrum Analysis Measures Medical Molecular Mus Muscle Muscle satellite cell Muscular Atrophy Mutate Natural regeneration Nicotinamide adenine dinucleotide Oncogenes Organ Organoids PHEMX gene Pathway interactions Pattern Population Post-Translational Protein Processing Process Proteins Protocols documentation Reporter Signal Transduction Site Skeletal Muscle Speed Supplementation System Testing Therapeutic Tissues Transcription Factor AP-1 Trauma Work adult stem cell aged aging population cofactor conditional knockout dietary supplements extracellular functional decline gain of function healing improved in vivo loss of function mouse model muscle aging muscle form muscle strength muscular system nicotinamide-beta-riboside novel therapeutic intervention novel therapeutics osteosarcoma overexpression pharmacologic programs regeneration potential regenerative regenerative tissue repaired response skeletal preservation stem cell function stem cells tissue repair transcription factor virtual young adult

ADP Ribose Transferases ADP ribosylation Address Adenosine Diphosphate Ribose Adult Affect Age Aging Automobile Driving Biology of Aging Cell Cycle Cell surface Clinic Consumption Data Deterioration Elderly Enzymes Event Exercise Functional disorder Gene Activation Gene Targeting Genes Genetic Health Hour Immunohistochemistry Injury Knockout Mice Laboratories LacZ Genes Left Mass Spectrum Analysis Measures Medical Molecular Mus Muscle Muscle satellite cell Muscular Atrophy Mutate Natural regeneration Nicotinamide adenine dinucleotide Oncogenes Organ Organoids PHEMX gene Pathway interactions Pattern Population Post-Translational Protein Processing Process Proteins Protocols documentation Reporter Signal Transduction Site Skeletal Muscle Speed Supplementation System Testing Therapeutic Tissues Transcription Factor AP-1 Trauma Work adult stem cell aged aging population cofactor conditional knockout dietary supplements extracellular functional decline gain of function healing improved in vivo loss of function mouse model muscle aging muscle form muscle strength muscular system nicotinamide-beta-riboside novel therapeutic intervention novel therapeutics osteosarcoma overexpression pharmacologic programs regeneration potential regenerative regenerative tissue repaired response skeletal preservation stem cell function stem cells tissue repair transcription factor virtual young adult

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项目摘要

Abstract One of the greatest mysteries in ageing biology is to understand why many tissues and organs in our body, including skeletal muscle, decline in function as we get older? Recent studies suggest that the inability of muscle stem cells (MuSCs) to turn on the repair program after trauma is a major factor leading to the loss of muscle mass and strength observed in the elderly. However, given that the signals driving MuSCs into the regenerative state remains a mystery even in young adults, we are left with virtually no therapeutic options for boosting the repair potential of aging MuSCs in the clinic. To address this unmet need, my laboratory recently discovered a new “Super-Healing” adult stem cell activation program, driven by the transcription factor, FBJ osteosarcoma oncogene (FOS), that speeds up adult stem cell activation and enhances muscle repair. Intriguingly, a key downstream target gene of FOS in adult MuSCs is the NAD-consuming, cell surface enzyme, ADP-Ribosyl-Transferase 1 (Art1), which attaches an understudied post-translational modification (PTM), mono-ADP-Ribosylation (MARylation), to protein substrates. Excitingly, our preliminary data suggests that the FOS/ART1-MARylation pathway is disrupted in aged MuSCs, and thus, representing one of the earliest molecular alterations that diminish the regenerative potential of aged skeletal muscle. Thus, in this proposal, we will test the hypothesis that the FOS/AP-1 tissue regenerative program (including the ART1 pathway) is mis-regulated in aged skeletal muscle, triggering a cascade of molecular events that dampen stem cell activation potential and lead to the progressive deterioration of skeletal muscle with increasing age; and most importantly, that reversal of this molecular dysfunction will correct the stem cell activation and regenerative deficits seen in aged skeletal muscle. In Aim1, we will determine the expression patterns and functional significance of FOS/AP-1 gene targets in adult and aged MuSCs. In Aim2, we will determine the expression dynamics, functional requirements, and MARylated protein substrates of the newly discovered NAD/ART1-MARylation stem cell activation pathway in adult and aged MuSCs. Collectively, this work will highlight a new FOS/NAD/ART1-MARylation stem cell activation pathway that has been largely ignored in aging biology until now and whose further study will open new therapeutic avenues for improving muscle health in the elderly population.

抽象的衰老生物学中最大的谜之一是了解为什么我们体内许多组织和器官包括骨骼肌，随着年龄的增长，功能下降？最近的研究表明，肌肉干细胞（MUSC）在创伤后打开修复程序是导致丧失的主要因素在古老的情况下观察到肌肉质量和力量。但是，考虑到将MUSC驱动到的信号即使在年轻人中，再生状态仍然是一个神秘的状态，我们几乎没有治疗选择提高诊所中衰老的MUSC的维修潜力。为了满足这种未满足的需求，我的实验室最近发现了一个新的“超级治疗”成人干细胞激活程序，该程序由转录因子FBJ驱动骨肉瘤癌基因（FOS），可以加快成人干细胞的激活并增强肌肉修复。有趣的是，成人MUSC中FOS的关键下游靶基因是NAD耗尽的细胞表面酶，ADP-核糖基 - 转移酶1（ART1），它附着在翻译后修饰（PTM），单ADP-核糖基化（MARYLATION），用于蛋白质底物。令人兴奋的是，我们的初步数据建议在老年MUSC中，FOS/Art1少量途径被破坏了，因此代表其中一种最早的分子改变减少了老化骨骼肌的再生潜力。那，这是提案，我们将检验以下假设：FOS/AP-1组织再生程序（包括ART1 途径）在老化的骨骼肌中被错误调节，引发了一系列该死的分子事件细胞活化潜力，并导致骨骼肌随着年龄的增长的进行性相对恶化；和最重要的是，这种分子功能障碍的逆转将纠正干细胞激活和在老年骨骼肌中看到的再生缺陷。在AIM1中，我们将确定表达模式和 FOS/AP-1基因靶标在成人和老年MUSC中的功能意义。在AIM2中，我们将确定新发现的表达动力学，功能需求和玛丽化的蛋白质底物成人和老年MUSC中的NAD/ART1降温干细胞活化途径。总的来说，这项工作将突出显示了一种新的FOS/NAD/ART1 Marylation干细胞激活途径，该途径在很大程度上被忽略到目前为止，衰老的生物学衰老，其进一步的研究将开放新的治疗途径，以改善肌肉老年人的健康。