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

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
批准号:
10657095
负责人:
Indranil Sinha
金额:
$39.52万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-04-01 至 2028-03-31

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中文摘要
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英文摘要
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.
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Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration
  • 批准号:
    10407512
  • 项目类别:
  • 资助金额:
    $24.2万
  • 财政年份:
    2018
  • 负责人:
    Indranil Sinha
  • 依托单位:
Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration
  • 批准号:
    10166755
  • 项目类别:
  • 资助金额:
    $24.2万
  • 财政年份:
    2018
  • 负责人:
    Indranil Sinha
  • 依托单位:
Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration
  • 批准号:
    9922193
  • 项目类别:
  • 资助金额:
    $24.2万
  • 财政年份:
    2018
  • 负责人:
    Indranil Sinha
  • 依托单位:
Reversing age-related dysfunction of skeletal muscle stem cells
  • 批准号:
    8035004
  • 项目类别:
  • 资助金额:
    $3.34万
  • 财政年份:
    2009
  • 负责人:
    Indranil Sinha
  • 依托单位:
海外基金