Metabolic dysfunction exacerbates astrogliosis and impairs motor recovery after experimental spinal cord injury
Kim H, Yoon H, Kleven A, Kleppe L, Lanza L, LeBrasseur N, Matveyenko A, Scarisbrick I
Mayo Clinic, Rochester, MN, United states
Objective: Metabolic syndrome is a well-recognized risk factor for the development of cardiovascular disease, type 2 diabetes, and neurodegenerative conditions, but there remains limited information regarding its impact on recovery of function after spinal cord injury (SCI). To address this gap in knowledge, we investigated the impact of systemic insulin resistance generated by diet-induced obesity in adult mice on neurobehavioral outcomes in an experimental compression model of incomplete SCI.
Design/Methods: To investigate the impact of high dietary fat consumption on recovery after experimental SCI, ten-week-old female C57BL6 mice were provided a regular diet (RD), or a diet high in fat and sucrose (HF) for 7 weeks prior to experimental compression SCI. Functional outcomes were monitored using Basso Mouse Scale (BMS) open field, incline plane test and bladder fullness determined prior to injury, 24 hr after SCI, and then weekly until 30 days post injury (dpi). Pathological correlates of changes in function were evaluated by examination of markers of inflammation and astrogliosis, in addition to the integrity of myelin, axons and synapses, both subacutely (14 d) and at more chronic 30 dpi end points.
Results: Mice consuming HF showed impairments in motor recovery evaluated by BMS score and subscore at 14 and 30 dpi, but not at earlier time points examined. Consumption of HF also impaired the mean maximal angle achieved on the incline plane test at 14, 21 and 30 dpi and resulted in significant impairments in bladder release. Immunochemical analysis of the spinal cord revealed a number of differences in markers of neural injury between the two groups. First, mice consuming HF exhibited significant increases in astrogliosis measured by glial fibrillary acidic protein (GFAP) prior to injury, compared to mice consuming a RD. In fact, the prominent increases in GFAP observed in the intact spinal cord of mice consuming HF were equivalent to those observed after SCI in mice consuming a regular chow. In the subacute period, markers of microglial/monocyte activation were elevated in all mice with SCI, however the increase was substantially greater in the spinal cord of mice consuming HF. The spinal cord white matter of mice consuming HF also showed reductions in the number of oligodendrocyte progenitor and mature myelinating cells prior to SCI and HF-associated reductions in myelin producing cells persisted at 14 and 30 dpi. In addition, loss of serotonergic axons in the spinal cord after SCI was exacerbated in mice consuming HF. Growth associated protein 43 (GAP43), a marker of axonal growth cones was elevated after SCI in the spinal cord of mice consuming a RD or a HF diet, however the magnitude of the increase in growth cones were severely impaired in mice consuming HF.
Conclusion: These findings identify diet induced obesity and insulin resistance as a risk factor for impaired neurobehavioral recovery at subacute and chronic time points after SCI and suggest the need to identify the mechanisms involved as potential targets for therapies to improve functional outcomes.
Support: NIH R01 NS052741, the Mayo Clinic Center for Biomedical Discovery and the Minnesota Spinal Cord Injury and Traumatic Brain Injury Research Grant Program.
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