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

项目概要/摘要 我感兴趣的是开发新的治疗策略，以维持肌肉质量和功能， 老年人口。我的实验室利用衰老的小鼠模型来研究衰老相关的 骨骼肌中缺氧信号的丢失影响维持肌肉质量的两个关键因素， 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 酶（PHD）2在骨骼肌中随着年龄的增长而显著增加，是缺氧的关键调节因子 信号通路这种骨骼肌PHD 2的增加导致缺氧诱导因子（HIF）-1（HIF-1 α）的丢失， 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， 衰老和基因修饰小鼠，我们已经证明，肌肉特异性增加PHD 2 概括了骨骼肌再生减少和有氧运动适应性丧失，如 衰老基于这些有趣的试验数据，该项目的中心目标是（1）机械地定义 PHD 2的作用及其对肌肉衰老再生的影响，（2）确定PHD 2是否抑制 随着年龄的增长保持骨骼肌肌源性潜力，和（3）评估是否增加骨骼肌PHD 2 限制了肌肉对有氧运动的适应性。重要的是，转录组分析在 人类也显示出老年骨骼肌中缺氧信号的减少，这表明翻译 潜在的缺氧信号靶点。由于FDA批准的PHD 2抑制剂是可获得的，因此改善了PHD 2抑制剂的活性。 对缺氧信号传导机制的理解，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， 衰老

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.