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，严重的亚病变骨脱矿和骨损伤 最近的研究表明，微结构会增加下肢骨折的风险。 机械负荷下，骨稳态是由肌因子、骨骼肌分泌的信号因子介导的。 肌因子，鸢尾素，通过含有蛋白 5 (FNDC5) 的纤连蛋白 III 型结构域的裂解产生，具有 在动物中，卸载会降低 FNDC5 基因表达，并与此相关。 小梁骨矿物质密度 (BMD) 损失表明鸢尾素/FNDC5 损伤是导致 此外，经证明，当发生 SCI 后骨质流失时，循环鸢尾素的增加可以减轻骨质流失。 在卸载过程中提供，并在卸载一段时间后提供，以刺激骨骼生长。 是治疗 SCI 患者骨质流失的一种有前途的治疗方法。 拟议研究的目标是进一步证明鸢尾素是 BMD 的关键决定因素，即 BMD 受损 irisin/FNDC5 机制导致 SCI 后骨质流失，并发现新的方式来利用 鸢尾素的全身成骨作用可改善 SCI 患者的肌肉骨骼康复策略。 拟议的研究将证明循环鸢尾素浓度和骨骼肌 FNDC5 表达与 BMD 和骨折风险相关，并且在 SCI 后这些相关性是否持续存在。 不成比例地影响骨小梁，并损害骨微结构、高分辨率外周 定量断层扫描 (HR-pQCT) 将用于评估小梁和皮质 BMD，并得出测量结果 与骨折风险相关，包括皮质孔隙度和骨衰竭负荷。 旨在证明 SCI 患者亚病变骨骼肌中 FNDC5 表达减少， 可能是由于 SCI 引起的纤维类型变化，因为运动刺激骨骼肌释放鸢尾素，并且 运动的成骨益处部分是由鸢尾素介导的，减少 FNDC5 表达可能会减弱 下半身运动对 SCI 患者的功效 上半身引起的循环鸢尾素增加。 运动可以增强下半身运动的成骨功效，因此，本研究的目的是。 检查手臂测力计高强度间歇运动对循环虹膜素的影响。 拟议的研究将确定鸢尾素/FNDC5机制是否会导致SCI后骨质流失以及 此外，研究结果还表明，基于运动的干预措施会减弱下半身的成骨反应。 确定上半身运动是否是增加鸢尾素循环的可行方法，并利用全身系统 鸢尾素对抗 SCI 后骨质流失的成骨作用。 Sterczala 博士作为运动生理学家的背景和培训为他提供了以下方面的专业知识 运动处方和规划，以及性能和骨骼肌适应的评估 该职业发展奖将提供与此相关的先进技术的培训。 骨矿物质密度、骨微结构的评估和骨生物力学的量化 此外，它将提供与 SCI 病理生理学和当前康复相关的培训。 改善 SCI 患者心脏代谢和肌肉骨骼健康的策略。 拥有与 SCI 患者一起进行研究、设计创新的基于运动的丰富经验 改善退伍军人健康和生活质量以及骨骼、内分泌和骨骼肌的方法 分析以更好地了解运动和病理生理状态对健康的影响。 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 对抗废用相关的肌肉骨骼损伤。