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.

项目摘要 衰老与骨骼系统的负面影响有关，导致骨骼健康受损， 脆弱和肌肉骨骼疾病的风险。然而，我们目前对这种机制的理解， 衰老对骨骼健康的影响有限。骨细胞是骨和骨骼中数量最多、寿命最长的细胞， 通过响应合成代谢信号（如机械负荷）来维持骨量的关键作用。此响应 老年骨的负荷因未知机制而受损，导致骨稳态紊乱。 随着年龄的增长，许多细胞和组织的能量代谢被破坏，但是能量代谢的调节 以及在老化过程中和机械负荷对骨细胞的影响仍不清楚。我们 初步发现已经确定合成代谢机械负荷调节骨细胞的能量代谢 在体外和体内。具体来说，脂肪酸β-氧化在应变反应中上调，这是关键。 β-氧化、过氧化物酶体增殖物激活受体δ（Pparδ）和肉毒碱的促进剂 棕榈酰转移酶1（Cpt 1）。体内骨细胞中Pparδ的缺失抑制β-氧化和骨减少 雌性小鼠但非雄性小鼠的质量。此外，与对照组相比， 年轻动物，和药理学激活的过氧化物酶体增殖物激活受体δ在老龄小鼠改善骨骼健康。这些发现 提示骨细胞能量代谢的重要功能，特别是β-氧化，在衰老的影响 和骨骼上的机械负荷。 在这个提议中，我们将确定骨细胞β-氧化在机械刺激反应中的作用 以及随着年龄的增长保持骨骼健康。对于这些研究，我们已经产生了具有靶向缺失的小鼠， 并将使用这些小鼠和来自年轻和老年小鼠的离体分离的骨细胞， 测定骨细胞β-氧化功能。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。在Aim中 3，我们将研究激活PPARδ以增加骨细胞中的β-氧化是否可以改善骨骼健康 老年小鼠 这些研究结果将显著增加对骨细胞能量代谢的认识 并确定了骨细胞中过氧化物酶体增殖物激活受体δ驱动的β-氧化的作用及其在老化和低老化过程中的功能。 机械负载