Osteocyte energy metabolism in aging

衰老过程中骨细胞的能量代谢

• 批准号: 10710207
• 负责人: Yukiko Kitase
• 金额: $ 54.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710207
• 关键词: Affect; Age; Age-Related Bone Loss; Aging; Attenuated; Biology; Bone Resorption; Carnitine Palmitoyltransferase I; Cell Respiration; Cells; Data; Economic Burden; Elderly; Energy Metabolism; Fatty Acids; Female; Fracture; Future; Goals; Health; Hip Fractures; Homeostasis; Impairment; In Vitro; Investigation; Knowledge; Lipids; Maintenance; Mechanical Stimulation; Mechanics; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular; Morbidity - disease rate; Mus; Musculoskeletal; Musculoskeletal Diseases; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Oxidative Phosphorylation; PPAR delta; Pathologic; Pathology; Pathway interactions; Patients; Play; Process; Production; Regulation; Risk; Role; Signal Transduction; Skeletal system; Skeleton; Source; Testing; Tissues; Woman; Work; age effect; age related; aged; antagonist; bone; bone aging; bone cell; bone health; bone loss; bone mass; fluid flow; frailty; improved; in vivo; juvenile animal; lifestyle intervention; mechanical load; men; mortality; negative affect; novel; novel strategies; oxidation; pharmacologic; prevent; promoter; response; shear stress; skeletal; therapeutic target; Affect; Age; Age-Related Bone Loss; Aging; Attenuated; Biology; Bone Resorption; Carnitine Palmitoyltransferase I; Cell Respiration; Cells; Data; Economic Burden; Elderly; Energy Metabolism; Fatty Acids; Female; Fracture; Future; Goals; Health; Hip Fractures; Homeostasis; Impairment; In Vitro; Investigation; Knowledge; Lipids; Maintenance; Mechanical Stimulation; Mechanics; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular; Morbidity - disease rate; Mus; Musculoskeletal; Musculoskeletal Diseases; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Oxidative Phosphorylation; PPAR delta; Pathologic; Pathology; Pathway interactions; Patients; Play; Process; Production; Regulation; Risk; Role; Signal Transduction; Skeletal system; Skeleton; Source; Testing; Tissues; Woman; Work; age effect; age related; aged; antagonist; bone; bone aging; bone cell; bone health; bone loss; bone mass; fluid flow; frailty; improved; in vivo; juvenile animal; lifestyle intervention; mechanical load; men; mortality; negative affect; novel; novel strategies; oxidation; pharmacologic; prevent; promoter; response; shear stress; skeletal; therapeutic target

PROJECT SUMMARY Aging is associated with negative effects on the skeletal system, leading to impaired bone health, increased frailty, and risk of musculoskeletal disorders. However, our current understanding of the mechanisms by which aging affects skeletal health is limited. Osteocytes are the most numerous and long-lived cells in bone and play key roles in maintaining bone mass by responding to anabolic signals such as mechanical loading. This response to loading is impaired in aged bone, by unknown mechanisms, leading to derangements in bone homeostasis. Energy metabolism is disrupted in many cells and tissues with aging, however regulation of energy metabolism in osteocytes and how this is affected during aging and by mechanical loading remains undefined. Our preliminary findings have identified that anabolic mechanical loading regulates energy metabolism in osteocytes in vitro and in vivo. Specifically, fatty acid β-oxidation is upregulated in response to strain, as are the key promoters of β-oxidation, peroxisome proliferator-activated receptor delta (Pparδ) and carnitine palmitoyltransferase 1 (Cpt1). Deletion of Pparδ in osteocytes in vivo inhibited β-oxidation and decreased bone mass in female mice but not males. Furthermore, β-oxidation is decreased in aged mouse bone compared to young animals, and pharmacological activation of PPARδ in aging mice improves bone health. These findings suggest important functions of osteocyte energy metabolism, and β-oxidation in particular, in the effects of aging and mechanical loading on bone. In this proposal, we will determine the role of osteocyte β-oxidation in the response to mechanical stimulation and the maintenance of bone health with aging. For these studies, we have generated mice with targeted deletion of Pparδ in osteocytes and will use these mice and ex vivo isolated osteocytes from young and aged mice to determine the function of β-oxidation in osteocytes. In Aim 1, we will determine the role of osteocyte β-oxidation in regulating bone health in young and aged mice. In Aim 2, we will determine how aging affects the metabolic response of osteocytes to mechanical loading and the role of PPARδ-driven β-oxidation in this process. In Aim 3, we will examine whether activation of PPARδ to increase β-oxidation in osteocytes can improve bone health in aged mice. The findings from the proposed studies will markedly increase the knowledge of osteocyte energy metabolism and define the role of PPARδ-driven β-oxidation in osteocytes and its function during aging and under mechanical loading.

项目摘要 衰老与对骨骼系统的负面影响有关，导致骨骼健康受损，增加 脆弱的肌肉骨骼疾病的风险。但是，我们当前对所在机制的理解 衰老会影响骨骼健康是有限的。骨细胞是骨骼中最多，长寿命的细胞，并且发挥作用 通过响应合成代谢信号（例如机械负载）来维持骨骼的关键作用。这个回应 老化的骨骼，未知机制会损害负载，从而导致骨稳态的进化。 能量代谢在许多衰老的细胞和组织中受到破坏，但是能量代谢的调节 在骨细胞中，以及在老化和机械负荷过程中如何影响这是不确定的。我们的 初步发现已经确定，合成代谢的机械负载调节骨细胞中的能量代谢 体外和体内。具体而言，脂肪酸β-氧化因应变而上调，关键也是如此 β氧化，过氧化物体增殖物激活的受体三角洲（PPARδ）和肉碱的启动子 棕榈酰转移酶1（CPT1）。在体内删除骨细胞中PPARδ抑制β-氧化并改善骨骼 雌性小鼠的质量，但不是雄性。此外，与 年轻动物和衰老小鼠PPARδ的药物激活改善了骨骼健康。这些发现 在衰老的作用中特别提出了骨细胞能代谢的重要功能，尤其是β氧化的作用 和机械载荷在骨头上。 在此提案中，我们将确定骨细胞β氧化在对机械刺激反应中的作用 以及随着衰老而维持骨骼健康。对于这些研究，我们已经产生了具有靶向缺失的小鼠 骨细胞中的PPARδ，并将使用这些小鼠和离体分离的年轻小鼠和老年小鼠的骨细胞 确定β-氧化在骨细胞中的功能。在AIM 1中，我们将确定骨细胞β-氧化的作用 在AIM 2中，我们将确定衰老如何影响代谢 骨细胞对机械负荷的反应以及PPARδ驱动的β氧化在此过程中的作用。目标 3，我们将检查PPARδ的激活是否增加骨细胞中的β氧化可以改善骨骼健康 在老年小鼠中。 拟议研究的发现将显着增加骨细胞能量代谢的知识 并定义PPARδ驱动的β-氧化在骨细胞中及其在衰老和下方的功能 机械载荷。