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，严重的亚绒毛骨脱矿化和骨骼受损 微体系结构增加了下限的骨折风险。最近的研究确定，除了 机械负荷，骨稳态是由肌动物，骨骼肌分泌的信号传导因素介导的。这 肌动物，irisin，是通过含有蛋白5（FNDC5）的纤连蛋白III型结构域的裂解产生的，具有 对骨形成的有效作用。在动物中，卸载会减少与FNDC5基因的表达 小梁骨矿物质密度（BMD）损失损害虹膜蛋白/FNDC5损害，作为有助于的机制 SCI后骨质流失。此外，已经证明增加循环虹膜蛋白可以减轻骨质的 在卸载后提供时提供并刺激骨骼生长。那，虹膜 是SCI个体骨质流失的有前途的治疗方法。 拟议的研究的目的是进一步证明Irisin是BMD的关键决定者 虹膜蛋白/FNDC5机制有助于SCI后骨骼流失，并发现新型的方式来利用 虹膜蛋白的系统性成骨作用改善SCI患者的肌肉骨骼康复策略。 拟议的研究将证明是否循环虹膜蛋白浓度和骨骼肌FNDC5 表达与BMD和断裂风险相关，如果这些相关性在SCI之后持续存在。鉴于那个科学 不成比例地影响小梁骨，损害骨微体系结构，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，并得出测量值 与断裂风险有关，包括皮质孔隙率和骨骼衰竭负荷。此外，拟议的研究 目的是证明在SCI的个体的亚属骨骼肌中，FNDC5表达降低 可能是由于SCI诱导的纤维类型变化所致。随着运动刺激骨骼肌释放虹膜蛋白，而 锻炼的成骨优势部分由虹膜蛋白介导，降低的FNDC5表达可能会减弱 下半身运动在SCI患者中的功效。上半身诱导的循环虹膜蛋白增加 运动可以提高下半身运动的成骨效率。拟议的研究旨在 检查对臂的高强度间隔运动对循环虹膜蛋白的作用。的发现 拟议的研究将确定虹膜蛋白/FNDC5机制是否有助于SCI后的骨质流失和 成骨反应的衰减是基于运动的下半身干预措施。此外，发现将 确定上身运动是否是增加循环虹膜蛋白并利用全身性的可行手段 虹膜蛋白在SCI后打击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有关的专业知识 锻炼处方和编程，以及对性能和骨骼肌适应的评估 锻炼。该职业发展奖将提供与该培训有关的高级技术培训 评估骨矿物质密度，骨微结构和骨生物力学数量的评估 特性。此外，它将提供与SCI和当前康复的病理生理学有关的培训 改善SCI患者心脏代谢和肌肉骨骼健康的策略。他的攻击团队 具有与SCI的人进行研究的丰富经验，设计基于创新的运动 改善退伍军人以及骨骼，内分泌和骨骼肌肉的健康和生活质量的方法 分析以更好地了解运动和病理生理状态对健康的影响。精神训练 团队和培训活动将有助于Sterczala博士实现成为一项独立研究的目标 科学家的重点是确定骨骼肌和骨骼影响的信号因素如何 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 打击废除相关的肌肉骨骼障碍。