Effects of Osteocyte Factors, WNT3a and PGE2, on Muscle with Aging

骨细胞因子 WNT3a 和 PGE2 对肌肉衰老的影响

基本信息

  • 批准号:
    10413018
  • 负责人:
  • 金额:
    $ 33.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-05-01 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Sarcopenia is the progressive loss of skeletal muscle mass and force/power that develops with aging. Accumulating data shows that it is principally the weakness that accompanies sarcopenia, not the loss of muscle size per se, that contributes to disability. We were the first group to propose that bone cells, specifically osteocytes, signal to muscle and play an important role in this process. We discovered that soluble factors from osteocytes from young mice (5 mo) accelerate myogenesis of both C2C12 cells and primary myoblasts, whereas no effect was observed with factors from osteocytes of aged mice (22 mo). We identified two known osteocyte factors, PGE2 and Wnt3a (i.e., osteokines), as potential mediators of osteocyte to muscle signaling, as they closely mimicked the effects of young osteocyte soluble factors on myogenesis. Both Wnt3a and PGE2 significantly upregulated genes that orchestrate growth, hypertrophy, mitochondrial biogenesis, and Ca2+- release/uptake in muscle. Wnt3a was associated with the translocation of β-catenin to nuclei and was linked to two downstream genes of the Wnt/β-catenin pathway, Fhl1 and Numb that have direct roles in myogenesis. Our cell based results were further supported by our ex vivo, in vivo and clinical studies. The conditional deletion of one allele of β-catenin in osteocytes led to a decrease in both muscle mass and function of skeletal muscles during aging, while conversely, skeletal muscle function was enhanced in the Lrp5G171V mouse, a model of increased skeletal Wnt/β-catenin signaling. Clinically, we have found that serum from healthy 60 yr old women, has high concentrations of WNT3a and increases myogenic differentiation of human primary myoblasts, while serum from osteoporotic women, which has 1/10 of the WNT3a serum levels of healthy women, decreases myogenesis. Ex vivo, PGE2 is able to mirror the effects of young osteocyte osteokines by enhancing force generation in young muscles, but not in aged muscles and the effects were linked to the expression of the EP4 receptor in muscles. Lipidomics profiling revealed that with age, levels of key lipid-signaling mediators of the arachidonic acid pathway decrease, however exercise rescues the levels of these lipids. These data suggest that with aging, bone to muscle signaling is defective or muscle response to PGE2 is impaired, potentially through EP4-PGE2 signaling in aged skeletal muscles. These studies support our hypothesis that bone to muscle signaling is altered with aging due to compromised Wnt/β-catenin and PGE2 signaling, contributing to sarcopenia-related muscle weakness. To test this hypothesis, we will conduct the following studies. Aim 1: Determine the role of Wnt/β-catenin signaling in bone-muscle crosstalk during aging/exercise. Aim 2: Determine the role of PGE2 signaling in bone-muscle crosstalk during aging/exercise. These studies will provide new mechanisms for regulation of muscle function by bone-signaling osteokines as well as provide a platform for new secreted factors involved in bone-muscle crosstalk during aging/exercise. These studies will generate important information for prevention and/or treatment of `osteosarcopenia'.
摘要

项目成果

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Marco Brotto其他文献

Marco Brotto的其他文献

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{{ truncateString('Marco Brotto', 18)}}的其他基金

Protecting the Diabetic Skeletal Muscle by Nampt Activation
通过 Nampt 激活保护糖尿病骨骼肌
  • 批准号:
    9903303
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Protecting the Diabetic Skeletal Muscle by Nampt Activation
通过 Nampt 激活保护糖尿病骨骼肌
  • 批准号:
    9764905
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Preserving Mitochondrial Function for Alleviating ALS Progression
保留线粒体功能以缓解 ALS 进展
  • 批准号:
    10609946
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Preserving mitochondrial function for alleviating ALS progression
保护线粒体功能以缓解 ALS 进展
  • 批准号:
    10366061
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Preserving mitochondrial function for alleviating ALS progression
保护线粒体功能以缓解 ALS 进展
  • 批准号:
    10155596
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Protecting the Diabetic Skeletal Muscle by Nampt Activation
通过 Nampt 激活保护糖尿病骨骼肌
  • 批准号:
    10368097
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Protecting the Diabetic Skeletal Muscle by Nampt Activation
通过 Nampt 激活保护糖尿病骨骼肌
  • 批准号:
    10597969
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Store-Operated Calcium Entry During Muscle Aging
肌肉衰老过程中钙库操纵的钙进入的调节
  • 批准号:
    9922210
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:
Loss of Numb in Muscle Dysfunction in Aging
衰老导致的肌肉功能障碍丧失麻木感
  • 批准号:
    9925170
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:
Loss of Numb in Muscle Dysfunction in Aging
衰老导致的肌肉功能障碍丧失麻木感
  • 批准号:
    10451758
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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