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

> **NIH VA IK1** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

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 programm...

## Key facts

- **NIH application ID:** 10993571
- **Project number:** 5IK1RX003641-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Adam J Sterczala
- **Activity code:** IK1 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993571

## Citation

> US National Institutes of Health, RePORTER application 10993571, The influence of irisin/FNDC5 on bone mineral density and fracture risk in individuals with spinal cord injury (5IK1RX003641-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10993571. Licensed CC0.

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