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

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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.