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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.

项目摘要/摘要我对开发新的治疗策略来维持肌肉质量和功能感兴趣。老年人口。我的实验室利用小鼠的衰老模型来研究衰老与骨骼肌缺氧信号的丢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；(2)适应有氧运动。脯氨酸羟基酶结构域随着年龄的增长，骨骼肌中的酶(PHD)2显著增加，是低氧的关键调节因子信号通路。这种骨骼肌PHD2的增加导致缺氧诱导因子-1的丢失，a 中枢转录因子负责下游低氧通路的信号传递。使用小鼠模型在衰老和转基因小鼠中，我们已经证明了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丧失，见衰老。在这些耐人寻味的试点数据的基础上，该项目的中心目标是(1)机械地定义 PHD2在衰老中的作用及其对肌肉再生的影响，(2)决定PHD2是否抑制随着年龄的增长保持骨骼肌生肌潜能，以及(3)评估骨骼肌PHD2是否增加随着年龄的增长，肌肉对有氧运动的适应能力受到限制。重要的是，转录组分析在人类在陈旧的骨骼肌中也表现出低氧信号的减少，这表明潜在的低氧信号靶点。随着FDA批准的PHD2抑制剂的上市，一种改进的低氧信号与骨骼肌再生和运动相关的机制研究反应可能为患有肌肉功能丧失的老年患者提供治疗机会衰老。