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PHD2 mediated loss of hypoxia signaling limits skeletal muscle regeneration and exercise response in aging

PHD2介导的缺氧信号丧失限制了骨骼肌再生和衰老过程中的运动反应

基本信息

批准号：
10657095
负责人：
Indranil Sinha
金额：
$ 39.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657095
关键词：
ARNT gene Activities of Daily Living Adverse event Aerobic Exercise Affect Aging Biological Blood capillaries Cell Nucleus Cell Survival Clinical Cytoplasm Data Down-Regulation Elderly Enzymes Exercise Exhibits FDA approved Fiber Gene Expression Genes Genetic Transcription Goals Hindlimb Human Hypoxia Hypoxia Inducible Factor Hypoxia Pathway Impairment Intervention Laboratories Maintenance Mediating Metabolic Pathway Mus Muscle Muscle function Muscle satellite cell Muscular Atrophy Myopathy Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Physiological Population Procollagen-Proline Dioxygenase Proteins Regenerative capacity Response Elements Role Signal Pathway Signal Transduction Skeletal Muscle Testing Therapeutic Up-Regulation adverse event risk adverse outcome angiogenesis density experimental study frailty functional decline improved inhibitor innovation interest mortality risk mouse model multicatalytic endopeptidase complex muscle form muscle regeneration notch protein novel novel therapeutics older patient overexpression pharmacologic regeneration potential response restoration sarcopenia skeletal skeletal muscle wasting skeletal preservation transcription factor transcriptome translational potential treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT I am interested in developing novel treatment strategies for maintaining muscle mass and function in the elderly population. My lab utilizes murine models of aging to investigate mechanisms on how aging-associated loss of hypoxia signaling in skeletal muscle affects two key factors in maintenance of muscle mass and function: (1) skeletal muscle regeneration and (2) adaptation to aerobic exercise. Prolyl hydroxylase domain enzyme (PHD)2 increases profoundly in skeletal muscle with aging and is a key regulator of the hypoxia signaling pathway. This increase in skeletal muscle PHD2 leads to loss of hypoxia inducible factor (HIF)-1, a central transcription factor responsible for downstream hypoxia pathway signaling. Using a murine model of aging and genetically modified mice, we have demonstrated that a muscle specific increase in PHD2 recapitulates diminished skeletal muscle regeneration and loss of aerobic exercise adaptation as seen in aging. Building on these intriguing pilot data, the central goals of this project are to (1) mechanistically define the role of PHD2 and its impact on muscle regeneration in aging, (2) determine whether PHD2 inhibition preserves skeletal muscle myogenic potential with aging, and (3) evaluate if increased skeletal muscle PHD2 in aging limits muscle adaptation in response to aerobic exercise. Importantly, transcriptome analysis in humans also demonstrates decreased hypoxia signaling in old skeletal muscle, suggesting translational potential for hypoxia signaling targets. As FDA approved PHD2 inhibitors are available, an improved mechanistic understanding of hypoxia signaling as it relates to skeletal muscle regeneration and exercise response may offer therapeutic opportunities for elderly patients suffering from loss of muscle function with aging.

项目概要/摘要我有兴趣开发新的治疗策略来维持肌肉质量和功能老年人口。我的实验室利用小鼠衰老模型来研究衰老相关的机制骨骼肌缺氧信号的丧失影响维持肌肉质量的两个关键因素和功能：（1）骨骼肌再生和（2）适应有氧运动。脯氨酰羟化酶结构域随着年龄的增长，骨骼肌中的酶 (PHD)2 显着增加，是缺氧的关键调节因子信号通路。骨骼肌 PHD2 的增加导致缺氧诱导因子 (HIF)-1 的丧失，这是一种负责下游缺氧途径信号传导的中央转录因子。使用小鼠模型在衰老和转基因小鼠中，我们已经证明 PHD2 的肌肉特异性增加概括了骨骼肌再生减少和有氧运动适应性丧失，如老化。基于这些有趣的试点数据，该项目的中心目标是 (1) 机械地定义 PHD2在衰老过程中的作用及其对肌肉再生的影响，（2）确定PHD2是否受到抑制随着年龄的增长，保留骨骼肌生肌潜力，并且 (3) 评估骨骼肌 PHD2 是否增加衰老限制了肌肉对有氧运动的适应。重要的是，转录组分析人类还表现出老年骨骼肌中缺氧信号的减少，这表明转化缺氧信号传导目标的潜力。随着 FDA 批准的 PHD2 抑制剂的出现，一种改进的对缺氧信号传导的机制理解，因为它与骨骼肌再生和运动有关反应可能为患有肌肉功能丧失的老年患者提供治疗机会老化。