The Relationship Between Irisin and Bone Health in Individuals With Spinal Cord Injury

After spinal cord injury (SCI), the severe sub-lesion bone loss increases lower-limb fracture risk. In addition to mechanical loading, bone homeostasis is mediated by myokines, skeletal muscle secreted factors, including irisin. This project aims to demonstrate that irisin is a key determinant of bone mineral density in sub-lesion bone, that impaired irisin mechanisms contribute to post-SCI bone loss, and identify novel modalities to leverage the osteogenic effects of irisin to improve musculoskeletal rehabilitation strategies for individuals with SCI.

The first aim of this project seeks to determine the relationship between circulating irisin and bone mineral density (BMD) in sub-lesion bones of individuals with SCI. Past research has reported positive correlations between irisin and BMD indicating that irisin is important factor in bone homeostasis. To date, the relationship between irisin and BMD, absent mechanical loading, as seen in individuals with SCI, has not been examined. Of note, irisin increases have been demonstrated to increase bone mass in healthy mice and prevent or reduce bone loss in mouse SCI models.

The second aim of this study seeks to determine if irisin concentrations are impaired as a result of pathologic changes in sub-lesion skeletal muscle after SCI. Irisin is released into circulation following cleavage of its precursor protein which is highly expressed in skeletal muscle. Generally, healthy human muscle demonstrates a mix of type I and type II muscle fibers, however, after SCI, there is a pathological transformation from type I to type II muscle. Given that irisin's precursor protein is more highly expressed in type I muscle, the post-SCI fiber type transformation could significantly attenuate circulating irisin concentrations and impair its downstream signaling effects. Understanding whether post-SCI fiber type shifts are associated with reduced circulating irisin could help explain the inefficacy of current rehabilitation methods.

The third aim of this study seeks to measure the irisin response to arm ergometer high intensity interval exercise. If circulating irisin concentrations are important to bone health, as current research suggests, then identifying a means in increase circulating irisin is essential to developing better musculoskeletal rehabilitation methods. While exercise has been demonstrated to increase circulating irisin, the exercise modalities performed (running, whole body resistance training) are not feasible for individuals with SCI. Arm ergometry exercise could provide a means to increase circulating concentrations of this osteogenic factor.

Inclusion criteria

Participants with SCI:

• age 18 years or older
• traumatic SCI at the cervical level 4 or lower that occurred at least 12 months prior to the start of the study
• American Spinal Injury Association Impairment Scale A, B or C
• uses a manual wheelchair as primary means of mobility (30+ hours per week)
• is able to perform a transfer independently to and from a wheelchair
• has adequate strength and upper extremity function to operate an arm ergometer

Control Participants:

• age and sex-matched to participant with SCI

Exclusion criteria

Participants with SCI:

• active use of medications which potentially affect bone metabolism, including: parathyroid hormone and analogs, androgenic or estrogenic steroids, bisphosphonates, oral glucocorticoids (use for more than 3 months)
• history of fractures or dislocations in the upper extremity from which the participant has not fully recovered
• upper limb pain or injury that interferes with the ability to perform aerobic exercise
• recent hospitalization for any reason (within the past three months)
• history of coronary artery disease, coronary bypass surgery or other cardiorespiratory events or conditions
• likely to experience clinically significant autonomic dysreflexia and/ or orthostatic hypotension in response to vigorous exercise
• endocrinopathy or metabolic disorders of the bone

• e.g. Paget's disease, renal bone disease
• history of allergic reaction to lidocaine
• any other conditions that the person's primary care physician deems is a contraindication to participation in arm ergometry exercise stress testing or vigorous exercise
• pregnant
• participation in another "Greater than Minimal Risk" study.

Control Participants:

• active use of medications which potentially affect bone metabolism, including: parathyroid hormone and analogs, androgenic or estrogenic steroids, bisphosphonates, oral glucocorticoids (use for more than 3 months)
• history of neuromuscular conditions which could influence muscle gene expression
• history of lower body musculoskeletal injuries from which the participant has not fully recovered
• recent hospitalization for any reason (within the past three months)
• history of allergic reaction to lidocaine
• any other conditions that the person's primary care physician deems is a contraindication to the performance of a vastus lateralis muscle biopsy
• pregnant
• participation in another "Greater than Minimal Risk" study