Osteocyte energy metabolism in aging

衰老过程中骨细胞的能量代谢

• 批准号: 10585661
• 负责人: Yukiko Kitase
• 金额: $ 41.21万
• 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/10585661
• 关键词: Affect; Age; Age-Related Bone Loss; Aging; Attenuated; Biology; 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; Lead; Light; 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; Pharmacology; 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; 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.

项目概要 衰老与骨骼系统的负面影响有关，导致骨骼健康受损，增加 虚弱和肌肉骨骼疾病的风险。然而，我们目前对机制的理解 衰老对骨骼健康的影响是有限的。骨细胞是骨骼和游戏中数量最多、寿命最长的细胞 通过响应机械负荷等合成代谢信号，在维持骨量方面发挥关键作用。这个回应 由于未知的机制，老化骨骼的负荷能力受到损害，导致骨骼稳态紊乱。 随着衰老，许多细胞和组织的能量代谢受到破坏，但是能量代谢的调节 在骨细胞中，以及在衰老过程中和机械负荷下其如何受到影响仍不清楚。我们的 初步研究结果表明，合成代谢机械负荷调节骨细胞的能量代谢 体外和体内。具体来说，脂肪酸 β-氧化会因应变而上调，这是关键 β-氧化、过氧化物酶体增殖物激活受体 δ (Pparδ) 和肉碱的促进剂 棕榈酰转移酶 1 (Cpt1)。体内骨细胞中 Pparδ 的缺失抑制了 β-氧化并减少了骨量 雌性小鼠有肿块，但雄性小鼠没有。此外，与其他小鼠相比，老年小鼠骨骼中的 β-氧化作用有所减少 年轻动物和衰老小鼠中 PPARδ 的药理激活可改善骨骼健康。这些发现 表明骨细胞能量代谢，特别是β-氧化在衰老影响中的重要功能 以及骨骼上的机械负荷。 在本提案中，我们将确定骨细胞 β-氧化在机械刺激反应中的作用 以及随着衰老维持骨骼健康。对于这些研究，我们培育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来自年轻和老年小鼠的离体分离骨细胞来 确定骨细胞中β-氧化的功能。在目标 1 中，我们将确定骨细胞 β-氧化的作用 调节年轻和老年小鼠的骨骼健康。在目标 2 中，我们将确定衰老如何影响新陈代谢 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。瞄准 3、我们将检查激活PPARδ以增加骨细胞中的β-氧化是否可以改善骨骼健康 在老年小鼠中。 拟议研究的结果将显着增加对骨细胞能量代谢的了解 并定义 PPARδ 驱动的 β-氧化在骨细胞中的作用及其在衰老和低龄状态下的功能 机械加载。