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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

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.

摘要