Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation.

Ganchimeg Davaa,Kwonho Hong,Jin Young Hong,Seong Jae Lee,Seo Young Kim,Jung Keun Hyun,Tae Uk Kim

doi:10.3390/cells10010143

Ganchimeg Davaa, Kwonho Hong + Show 5 more

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https://doi.org/10.3390/cells10010143

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Abstract

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

Highlights

Spinal cord injury (SCI) is a major devastating lesion, and neurological recovery after spinal cord injury (SCI) is rarely seen in the clinical setting
We aimed to investigate whether treadmill exercise promotes histological and functional recovery in rats subjected to SCI and whether epigenetic changes are related to these results
We investigated DNA methylation changes in the brain motor cortex at 12 weeks after injury in both the control and exercise groups. 5mC and 5hmC within neurons in the brain motor cortex were identified using immunohistochemical double-staining (Figure 3a,b), and we found that the anti-5mC and anti-5hmC intensities within NeuN-positive neurons were higher in the exercise group than those in the control group

Summary

Introduction

Spinal cord injury (SCI) is a major devastating lesion, and neurological recovery after SCI is rarely seen in the clinical setting. The main reason for locomotor training in SCI patients was initially to maximize the remaining muscle function to replace the impaired function caused by disconnected motor tracts in the spinal cord. Some researchers have reported functional recovery after exercise training in animal SCI models, and they explained this phenomenon in three ways: compensation, regeneration, and neuronal plasticity. Numerous previous studies reported an increase in neuronal plasticity after locomotor training, with upregulation of various neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the spinal cord [4,5] and BDNF, microtubuleassociated protein 2 (MAP-2), and synaptophysin in the motor cortex [6], or modulation of the phosphatase and tensin homolog (PTEN)/mammalian target of rapamycin (mTOR)

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