Ottawa study highlights neuroprotective effect of running in mouse model of neurodegeneration, identifies key mediating protein
Physical exercise – in particular resistance training such as lifting weights, and cardiovascular or aerobic training such as running and swimming – has become a key component to the management of multiple sclerosis (MS). The MS research community has come a long way from viewing exercise as harmful to now seeing exercise as a helpful way to cope with symptoms and improve overall health. The question now remains: can physical exercise alter and/or improve the underlying MS disease?
Researchers from Dr. David Picketts’ laboratory at the Ottawa Hospital Research Institute have published compelling evidence which demonstrates that running can delay progression of neurodegeneration and promote repair. This work, published earlier this month in Cell Reports, was done primarily in a mouse model that exhibits nerve damage in part of the brain (the cerebellum) and loss of motor function. Lead author Dr. Matías Alvarez-Saavedra and his team used this mouse model to examine the effects of exercise on repair, neuroprotection and neurodegeneration, and identified a protein that could play an important role.
Through genetic manipulation, Dr. Alvarez-Saavedra’s team developed a mouse model that exhibited nerve cell death, impaired mobility, reduced weight gain and shorter survival. Given previous research findings showing that physical exercise can influence repair and curb neurodegeneration, the researchers hypothesized that their mouse would experience improvements following exercise and be a good model to study potential mechanisms that could explain the observed response.
They first provided the mice with access to a running wheel, which the mice used without being prompted, and made observations of changes in survival, balance, weight and functioning following voluntary running. Next, the researchers analyzed brain samples from the mice and compared them to samples from genetically modified mice who did not have access to a running wheel, as well as normal mice (not genetically modified). They measured specific markers of oligodendrocyte development and myelin production. Finally, the researchers looked at levels of specific genes and proteins, to determine if any of them are influenced by exercise and, if so, can they contribute to repair and neuroprotection in the central nervous system.
The researchers found that, in the genetically modified mice that exhibited neurodegeneration and mobility impairment, voluntary running prolonged survival, increased weight gain, showed daily improvements in distance travelled, and reduced motor deficits.
When they looked at brain samples, the researchers found that measures of oligodendrocyte development were increased in the damaged cerebellum following running, suggesting that oligodendrocyte production may be contributing to the recovery of the mice following exercise. Markers of fully developed oligodendrocytes were also increased in the running mice compared with mice who did not run and normal (non-genetically altered) mice.
When they investigated whether increased oligodendrocyte numbers promoted myelin production, the researchers found myelin surrounding the less matured versions of the oligodendrocytes (precursor cells), which was not present in inactive mice. They speculated that increased myelination protects the nerve cells in the cerebellum and strengthens their function.
Gene sequencing studies revealed close to 2,300 genes that had increased expression. Among them were genes related to neurotransmission (nerve communication) and nerve functioning and survival. In particular, they confirmed previous findings that a specific nerve protein called VGF was found in greater numbers in running mice versus their inactive siblings.
The researchers also found that VGF stimulated production and development of oligodendrocytes, which could potentially explain why the mice improved in condition following voluntary running. In addition to influencing oligodendrocytes, VGF also has an anti-depressant effect and maintains levels of proteins that promote nerve survival and brain function.
Overall, this work demonstrated that, in a mouse model of mobility dysfunction and neurodegeneration, running promoted the healthy survival and functioning of nerve cells, by enabling the production of myelin and encouraging the development of cells that produce myelin. The research group has also highlighted VGF as a key player in this neuroprotective process, which does not come as a surprise since exercise has been previously shown to increase levels of VGF. This work is especially relevant to MS, where myelin damage leads to an array of neurological symptoms and irreversible disability. What is more, repair appears to be stunted or slowed in MS, and so encouraging oligodendrocyte development and myelin production should be a top therapeutic priority.
This study shows that running may have a direct impact on repair and neuroprotection in the central nervous system, adding to a growing body of evidence supporting the positive benefits of physical exercise in MS. The MS Society of Canada recently awarded Dr. Picketts with funding for the next phase of this work, which will explore in further detail how VGF stimulates myelin repair and identify drugs that could tap into this pathway and promote remyelination.
Alvarez-Saavedra M. et al. (2016) Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice. Cell Reports: 17(3), 862-875.