The efficacy of β-aminoisobutyric acid myokine to reduce bone loss after spinal cord injury

β-氨基异丁酸肌因子减少脊髓损伤后骨丢失的功效

• 批准号: 10400101
• 负责人: HESHAM A TAWFEEK
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400101
• 关键词: Acute; Aminoisobutyric Acids; Animal Model; Animals; Applications Grants; Architecture; Attenuated; Biochemical; Biological Assay; Biomechanics; Bone Density; Bone Growth; Bone Marrow; Bone structure; Cell physiology; Cellular Structures; Chronic; Clinical; Collaborations; Consumption; Data; Development; Devices; Disabled Persons; Distal; Dose; Dual-Energy X-Ray Absorptiometry; Environment; Enzyme-Linked Immunosorbent Assay; Exercise; Exhibits; Female; Femur; Fracture; Healthcare; Hindlimb Suspension; Immobilization; Impairment; Individual; Injury; Knee; Lesion; Lipid Peroxidation; Longevity; Lower Extremity; Measurement; Measures; Mediating; Medical center; Mitochondria; Modeling; Motor; Mus; Muscle; Musculoskeletal System; Names; Operative Surgical Procedures; Oral Administration; Osteocytes; Osteoporosis; Outcome; Oxidative Stress; Paralysed; Patients; Pharmaceutical Preparations; Physical activity; Pre-Clinical Model; Property; Quality of life; Randomized; Research Personnel; Resource Sharing; Risk; Scanning; Scientist; Site; Skeleton; Spinal Cord Contusions; Spinal cord injury; Stress; Structure; Tail; Testing; Therapeutic; Veterans; Walking; Wild Type Mouse; Work; authority; bone; bone cell; bone loss; bone mass; bone quality; bone strength; bone turnover; carbohydrate metabolism; drinking water; exoskeleton device; experience; experimental study; fracture risk; fragility fracture; high risk; improved; insight; lipid metabolism; male; member; microCT; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; osteogenic; powered exoskeleton; prevent; protective effect; skeletal; tibia; tomography

Veterans with chronic motor complete spinal cord injury (SCI) invariably have had bone loss and resultant severe sub-lesional osteoporosis and increased fragility fractures. Currently, there is no widely accepted or proven treatment for osteoporosis in non-ambulatory patients with SCI. The efficacy of anti-resorptive agents in the treatment of those with acute SCI has been questioned and ineffective. As a result, there is an urgent need to develop new therapeutic strategies to prevent bone loss and enhance bone quality after sustaining a SCI. The primary objective of this proposal is to determine the efficacy of a recently-discovered muscle factor or myokine named β-aminoisobutyric acid (BAIBA) on reducing bone loss after chronic SCI. BAIBA has been shown to exhibit potent osteogenic properties and to prevent bone loss in tail suspended mice, a model of unloading bone loss. Furthermore, BAIBA produced its favorable osteogenic properties by inhibiting, in osteocytes, oxidative stress and improving mitochondrial function. Importantly, our preliminary findings demonstrate that osteocytes from bones of SCI mice exhibit impaired mitochondrial function and increased oxidative stress. Accordingly, we propose to test the hypothesis that BAIBA administration will restore osteocyte function thus reducing bone loss after chronic SCI. In our study aim, we will elucidate the effects of oral administration of vehicle and different doses of BAIBA on restoring bone mineral density (BMD) and structure in mice after chronic SCI. BAIBA will be administered to 20 week old C57BL/6J wild type male and female sham or SCI mice in drinking water at 0, 50, 100, or 500 mg/kg/day. Treatment will start 35 days after SCI and will continue for 35 days when animals will be sacrificed. Endpoint analyses will include measurement of BMD by Dual energy x-ray absorptiometry (DXA) scanning and bone structure and microarchitecture by microcomputed tomography scanning (Micro-CT). Biochemical analysis of bone turnover markers and factors will also be performed on collected sera and bone marrow (BM) supernatants using specific ELISA. Mechanistically, the effects of BAIBA treatment on oxidative stress will be evaluated on BM supernatants and osteocyte-enriched bone extracts of SCI and control mice using specific oxidative stress assays. The project is expected to identify the optimal therapeutic dose of BAIBA that will attenuate the deleterious effects of immobilization on the skeleton of SCI animals. This application has the potential of discovering a new therapeutic strategy that may overcome the challenge of severe osteoporosis in Veterans with SCI specifically many years after injury. We propose the following specific aim: Aim: To determine the effects of BAIBA on restoring skeletal integrity after chronic SCI.

患有慢性运动性完全脊髓损伤 (SCI) 的退伍军人总是会出现骨质流失并导致骨质流失。 严重的病灶下骨质疏松和骨折脆性增加目前尚无广泛接受或认可的方法。 抗再吸收药物对非卧床 SCI 患者骨质疏松症的有效治疗。 急性 SCI 患者的治疗受到质疑且效果不佳，因此迫切需要。 开发新的治疗策略，以防止脊髓损伤后骨质流失并提高骨质量。 该提案的主要目标是确定最近发现的肌肉因子或 名为 β-氨基异丁酸 (BAIBA) 的肌因子可减少慢性 SCI 后的骨质流失。 显示出有效的成骨特性并防止尾悬小鼠模型中的骨质流失 此外，BAIBA 通过抑制，产生其有利的成骨特性。 重要的是，我们的初步发现。 证明来自 SCI 小鼠骨骼的骨细胞表现出线粒体功能受损和线粒体功能增加 因此，我们建议检验 BAIBA 给药将恢复氧化应激的假设。 骨细胞功能，从而减少慢性 SCI 后的骨质流失。在我们的研究目的中，我们将阐明其影响。 口服媒介物和不同剂量的 BAIBA 对恢复骨矿物质密度 (BMD) 和 慢性 SCI 后小鼠的结构将给予 20 周龄的 C57BL/6J 野生型雄性和 雌性假手术或 SCI 小鼠以 0、50、100 或 500 mg/kg/天的剂量饮用水，治疗将在 35 天后开始。 SCI 将持续 35 天，届时将处死动物，终点分析将包括测量。 通过双能 X 射线吸收测定法 (DXA) 扫描测定 BMD，并通过 骨转换标志物和因素的显微计算机断层扫描（Micro-CT）。 还将使用特定的 ELISA 对收集的血清和骨髓 (BM) 上清液进行检测。 从机制上讲，BAIBA 治疗对氧化应激的影响将通过 BM 上清液和 使用特定的氧化应激测定对 SCI 小鼠和对照小鼠的富含骨细胞的骨提取物进行研究。 预计将确定 BAIBA 的最佳治疗剂量，以减轻 BAIBA 的有害影响 固定在 SCI 动物的骨骼上这一应用有可能发现一种新的方法。 可以克服 SCI 退伍军人严重骨质疏松症挑战的治疗策略 我们提出以下具体目标： 目的：确定 BAIBA 对慢性 SCI 后恢复骨骼完整性的作用。