Running triggers production of a molecule that repairs the brain in animal models


Running triggers production of a molecule that repairs the brain in animal models
Researchers at the Ottawa Hospital and the University of Ottawa have discovered that a molecule triggered by running can help repair certain kinds of brain damage in animal models. The team includes (from left) Dr. Rashmi Kothary, Dr. Robin Parks, Yves De Repentigny, Keqin Yan and Dr. David Picketts. 

Researchers at The Ottawa Hospital and the University of Ottawa have discovered that a molecule triggered by running can help repair certain kinds of brain damage in animal models. They found that this molecule, called VGF nerve growth factor, helps to heal the protective coating that surrounds and insulates nerve fibres. Their study, published in Cell Reports, could pave the way for new treatments for multiple sclerosis and other neurodegenerative disorders that involve damaged nerve insulation.

 However, if these mice were given the opportunity to run freely on a wheel, they lived over 12 months, a more typical mouse lifespan. The running mice also gained more weight and acquired a better sense of balance compared to their sedentary siblings. However, they needed to keep exercising to maintain these benefits. If the running wheel was removed, their symptoms came back and they did not live as long.

Looking at their brains, the researchers found that the running mice gained significantly more insulation in their cerebellum compared to their sedentary siblings.

To find out why running was causing this insulation, the team looked for differences in gene expression between the running and sedentary mice and identified VGF as a prime candidate. VGF is one of the hundreds of molecules that muscles and the brain release into the body during exercise. It also has an anti-depressant effect that helps make exercise feel good.

When the research team used a non-replicating virus to introduce the VGF protein into the bloodstream of a sedentary mutant mouse, the effects were similar to having the mouse run – more insulation in the damaged area of the cerebellum, and fewer disease symptoms.

“We saw that the existing neurons became better insulated and more stable,” said Dr. Matías Alvarez-Saavedra, the lead author on the paper. “This means that the unhealthy neurons worked better and the previously damaged circuits in the brain became stronger and more functional.”

Dr. Alvarez-Saavedra obtained his PhD in Dr. Picketts’ research group, and is currently a postdoctoral fellow at the New York University School of Medicine and the Howard Hughes Medical Institute.

“We need to do broader research to see whether this molecule can also be helpful in treating and other neurodegenerative diseases,” said Dr. Picketts.

 

Highlights

  • Running promotes the survival of mice with cerebellar ataxia following Snf2h inactivation
  • Running ataxic mice show enhanced oligodendrogenesis and de novo myelination
  • Comparative RNA-seq studies identify VGF as a contributor to brain repair
  • VGF overexpression improves ataxic phenotype in mice without exercise

Summary

Exercise has been argued to enhance cognitive function and slow progressive neurodegenerative disease. Although exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene impairs cerebellar development producing mice with poor motor function, progressive ataxia, and death between postnatal days 25–45. Here, we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides promote oligodendrogenesis in vitro, whereas Snf2h cKO mice treated with full-length VGF-encoding adenoviruses removed the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the CNS.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.