The influence of irisin/FNDC5 on bone mineral density and fracture risk in individuals with spinal cord injury

鸢尾素/FNDC5对脊髓损伤个体骨矿物质密度和骨折风险的影响

• 批准号: 10609491
• 负责人: Adam J Sterczala
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609491
• 关键词: Acute; Affect; Age; American; Animal Experimentation; Animals; Attenuated; Biomechanics; Biopsy; Blood specimen; Bone Density; Bone Growth; Disease; Distal; Endocrine; Enzyme-Linked Immunosorbent Assay; Exercise; Failure; Fast-Twitch Muscle Fibers; Femur; Fiber; Fibronectins; Finite Element Analysis; Fracture; Functional disorder; Gene Expression; Goals; Health; Homeostasis; Hormonal; Human; Impairment; Individual; Injections; Intervention; K-Series Research Career Programs; Lesion; Lower Extremity; Mass Spectrum Analysis; Measures; Mediating; Mentorship; Metaphysis; Methods; Modality; Muscle; Muscle Fibers; Musculoskeletal; Myosin Heavy Chains; Myosin S-1; Osteoclasts; Osteogenesis; Paralysed; Performance; Peripheral; Polymerase Chain Reaction; Porosity; Property; Proteins; Quality of life; Rehabilitation therapy; Research; Resolution; Rest; Reverse Transcription; Scanning; Scientist; Signal Transduction; Skeletal Muscle; Skeletal bone; Spinal cord injury; Techniques; Therapeutic; Training; Training Activity; Veterans; Weight-Bearing state; Western Blotting; Work; arm; attenuation; bone; bone fragility; bone health; bone loss; cardiometabolism; combat; comparison control; cortical bone; demineralization; design; exercise intensity; exercise physiologist; exercise prescription; experience; fracture risk; functional electrical stimulation; improved; innovation; intraperitoneal; male; mechanical load; mode of exercise; novel; novel strategies; osteoblast differentiation; osteogenic; prevent; rehabilitation strategy; release factor; response; substantia spongiosa; success; tibia; tomography; vastus lateralis

After spinal cord injury (SCI), the severe sub-lesion bone demineralization and impairment of bone microarchitecture increases lower-limb fracture risk. Recent research has determined that in addition to mechanical loading, bone homeostasis is mediated by myokines, skeletal muscle secreted signaling factors. The myokine, irisin, produced via the cleavage of fibronectin type III domain containing protein 5 (FNDC5), has a potent effect on bone formation. In animals, unloading reduces FNDC5 gene expression in correlation with trabecular bone mineral density (BMD) loss implicating irisin/FNDC5 impairment as a mechanism contributing to post-SCI bone loss. Additionally, increased circulating irisin has been demonstrated to attenuate bone loss when provided during unloading and to stimulate bone growth when provided after a period of unloading. Thus, irisin is a promising therapeutic approach for bone loss in individuals with SCI. The goal of the proposed research is to further demonstrate that irisin is a key determinant of BMD, that impaired irisin/FNDC5 mechanisms contribute to bone loss after-SCI, and discover novel modalities to leverage the systemic osteogenic effects of irisin to improve musculoskeletal rehabilitation strategies for individuals with SCI. The proposed research will demonstrate if circulating irisin concentrations and skeletal muscle FNDC5 expression are correlated with BMD and fracture risk, and if these correlations persist after SCI. Given that SCI disproportionately affects trabecular bone, and impairs bone microarchitecture, high-resolution peripheral quantitative tomography (HR-pQCT) will be used to assess trabecular and cortical BMD, and derive measures associated with fracture risk including cortical porosity and bone failure load. Additionally, the proposed research aims to demonstrate that FNDC5 expression is reduced in sub-lesion skeletal muscle of individuals with SCI, likely due to SCI-induced fiber type changes. As exercise stimulates irisin release by skeletal muscle, and the osteogenic benefits of exercise are partly mediated by irisin, reduced FNDC5 expression could attenuate the efficacy of lower body exercise in individuals with SCI. Increases in circulating irisin induced by upper body exercise could enhance the osteogenic efficacy of lower body exercise. Thus, the proposed research aims to examine to effect of arm ergometer high-intensity interval exercise on circulating irisin. The findings of the proposed research will determine if irisin/FNDC5 mechanisms contribute to post-SCI bone loss and the attenuation of osteogenic responses lower body exercise-based interventions. Additionally, the findings will determine if upper body exercise is a viable means to increase circulating irisin, and leverage the systemic osteogenic effect of irisin to combat bone loss after SCI. Dr. Sterczala’s background and training as an exercise physiologist has provided him with expertise regarding exercise prescription and programming, and the assessment of performance and skeletal muscle adaptations to exercise. This career development award would provide training in advanced techniques related to the assessment of bone mineral density, bone microarchitecture and the quantification of bone biomechanical properties. Additionally, it would provide training related to the pathophysiology of SCI and current rehabilitative strategies to improve cardiometabolic and musculoskeletal health in individuals with SCI. His mentorship team has extensive experience conducting research with individuals with SCI, designing innovative exercise-based approaches to improve health and quality of life for Veterans, as well as bone, endocrine, and skeletal muscle analyses to better understand the impact of exercise and pathophysiological states on health. The mentorship team and training activities would aid Dr. Sterczala achieve his goals of becoming an independent research scientist with a focus on determining how signaling factors secreted by skeletal muscle and bone influence musculoskeletal health and how these factors may be leveraged to develop innovative rehabilitative strategies to combat disuse associated musculoskeletal impairment.

脊髓损伤(SCI)后，严重的亚病变骨脱钙和骨损伤 微结构增加了下肢骨折的风险。最近的研究已经确定，除了 机械负荷时，骨骼动态平衡是由肌动因子、骨骼肌分泌的信号因子介导的。这个 通过裂解纤维连接蛋白III型结构域含蛋白5(FNDC5)而产生的肌动蛋白虹膜蛋白具有一种 对骨形成有很强的作用。在动物中，卸货降低FNDC5基因的表达与 骨小梁骨密度(BMD)丢失与虹膜蛋白/FNDC5功能受损有关 脊髓损伤后骨质丢失。此外，在以下情况下，增加循环虹膜已被证明可以减轻骨丢失。 在卸载过程中提供，并在卸载一段时间后提供时刺激骨骼生长。因此，淫羊藿苷 是治疗脊髓损伤患者骨丢失的一种有前景的治疗方法。 拟议研究的目标是进一步证明淫羊藿素是BMD的一个关键决定因素，即 虹膜蛋白/FNDC5机制有助于脊髓损伤后的骨丢失，并发现新的方式来利用 虹膜蛋白的全身性成骨作用改善脊髓损伤患者的肌肉骨骼康复策略。 这项拟议的研究将证明循环虹膜蛋白浓度和骨骼肌FNDC5 表达与BMD和骨折风险相关，以及这些相关性在脊髓损伤后是否持续。鉴于那次SCI 不成比例地影响骨小梁，损害骨的微结构，高分辨率外周 定量断层扫描(HR-pQCT)将用于评估骨小梁和皮质骨密度，并得出测量结果 与骨折风险相关，包括皮质孔洞和骨破坏负荷。此外，拟议的研究 目的是证明FNDC5在脊髓损伤个体病变下骨骼肌中的表达减少， 可能是由于脊髓损伤引起的纤维类型改变。因为运动刺激骨骼肌释放虹膜蛋白，而 运动的成骨益处部分是通过虹膜蛋白介导的，降低FNDC5的表达可能会减弱 下体运动对脊髓损伤患者的疗效。上半身引起的循环虹膜蛋白增加 运动可增强下体运动的成骨效果。因此，拟议的研究旨在 检测臂测功大强度间歇运动对循环虹膜的影响。调查结果： 拟议的研究将确定虹膜蛋白/FNDC5机制是否有助于脊髓损伤后的骨丢失和 基于下体运动的干预措施对成骨反应的减弱。此外，调查结果将 确定上半身运动是否是增加循环虹膜的可行方法，并利用全身 淫羊藿素抗脊髓损伤后骨丢失的成骨作用。 斯特尔扎拉博士作为一名运动生理学家的背景和训练为他提供了关于 运动处方和规划，以及对运动成绩和骨骼肌适应能力的评估 锻炼身体。该职业发展奖将提供与以下方面相关的高级技术培训 骨密度、骨微结构和骨生物力学定量研究 属性。此外，它还将提供与脊髓损伤的病理生理学和当前康复治疗有关的培训。 改善脊髓损伤患者心脏代谢和肌肉骨骼健康的策略。他的导师团队 有丰富的与脊髓损伤患者进行研究的经验，设计创新的基于锻炼的 改善退伍军人健康和生活质量的方法，以及骨骼、内分泌和骨骼肌 分析以更好地了解运动和病理生理状态对健康的影响。导师制 团队和培训活动将帮助Sterczala博士实现成为独立研究人员的目标 专注于确定骨骼肌和骨骼分泌的信号因子如何影响的科学家 肌肉骨骼健康以及如何利用这些因素来制定创新的康复策略 以对抗与废用相关的肌肉骨骼损伤。