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.

When Being a Doctor Is Similar to Running


Joy and pain are both part of the equation, says Jordan Grumet, MD

 Sometimes before I go on a run, I take the laces of my jogging shoes and tie them together in a knot. I wear the pair around my neck with each shoe falling to opposite sides. The heels clunk against my chest as I make my last minute rounds. It’s as if running is my job and the shoes are the instrument I use to perform that job. Eventually, I slip them off my neck, and onto my soul. It’s time to go running.

Today started in much the usual fashion. The first few blocks were rocky, but eventually, I established a pace. A mile in, I turned the corner, and I was on my beloved lakeside path. I could still feel the thumping on my chest. At first, I couldn’t help but smile. I was on the right path, the right journey. I passed fellow runners, and we shared a knowing glance. We were brothers and sisters, comrades in a common goal.

 As the miles continued, my joy began to fade. My feet burned, and my knees started to buckle. The sun battered my brow occasionally providing warmth, but often scalding. I passed my normal turning point but kept going. The pain faded and was replaced by a certain fatigue, a weariness. I was still uncomfortable, but I no longer cared.

Suddenly, I tripped on the shoelaces as if they were still tied together, and collapsed onto the pavement. For a moment, a dagger lanced through my hands and wrists before abating. The blood now dripped from my extremities.

But I was miles from the beginning; I couldn’t just stop.

My pace home was slow and methodical. The miles clicked by as my head hung down, no longer entranced by the joy of the lakeside path. I hid my eyes from my fellow joggers as they whisked by. I was embarrassed by my all too visible scars. My all too apparent pain.

I returned to the entrance of my house haggard and beat down. I no longer remembered neither the joy nor the pain of the journey I had just taken. Instead, I was empty.

 Had I taken the wrong path?

I climbed the steps and pushed the key into the lock. I sat on the bench in the mud room and took off the blood spattered shoes. For a moment, I went to tie the laces in a knot again and throw them around my neck.

Muscle memory.

Instead, I chucked the miserable pair unattached into the hallway closet.

Maybe it is time to stop running.

Dean Karnazes: the man who can run for ever.


Most runners have to stop when they reach their lactate threshold, but Dean Karnazesmuscles never tire: he can run for three days and nights without stopping. What’s his secret?

From club runners to Olympians, every athlete has a limit. Scientifically, this limit is defined as the body’s lactate threshold and when you exercise beyond it, running rapidly becomes unpleasant. We’ve all experienced that burning feeling – heart pounding, lungs gasping for air – as your muscles begin to fatigue, eventually locking up altogether as your body shuts down. However, there is one man whose physiological performance defies all convention:Dean Karnazes is an ultrarunner from California and, at times, it seems as if he can run forever.

Karnazes has completed some of the toughest endurance events on the planet, from a marathon to the South Pole in temperatures of -25C to the legendary Marathon des Sables, but in his entire life he has never experienced any form of muscle burn or cramp, even during runs exceeding 100 miles. It means his only limits are in the mind.

“At a certain level of intensity, I do feel like I can go a long way without tiring,” he says. “No matter how hard I push, my muscles never seize up. That’s kind of a nice thing if I plan to run a long way.”

When running, you break down glucose for energy, producing lactate as a byproduct and an additional source of fuel that can also be converted back into energy. However, when you exceed your lactate threshold, your body is no longer able to convert the lactate as rapidly as it is being produced, leading to a buildup of acidity in the muscles. It is your body’s way of telling you when to stop – but Karnazes never receives such signals.

Dean Karnazes running

“To be honest, what eventually happens is that I get sleepy. I’ve run through three nights without sleep and the third night of sleepless running was a bit psychotic. I actually experienced bouts of ‘sleep running’, where I was falling asleep while in motion, and I just willed myself to keep going.”

While supreme willpower is a common trait among ultrarunners, Karnazes first realised that he was actually biologically different when preparing to run 50 marathons in 50 days across the US back in 2006. “I was sent to a testing center in Colorado,” he recalls. “First, they performed an aerobic capacity test in which they found my results consistent with those of other highly trained athletes, but nothing extraordinary. Next, they performed a lactate threshold test. They said the test would take 15 minutes, tops. Finally, after an hour, they stopped the test. They said they’d never seen anything like this before.”

As Laurent Messonnier from the University of Savoie explains, the difference is that your aerobic capacity is a measure of your cardiovascular system performance, while your lactate threshold is your ability to clear lactate from your blood and convert it back into energy.

“If you take a high-level runner and you train that guy for a long time, his cardiovascular system will improve until a certain point where it will be very difficult to improve it further, as it’s determined by the heart and the blood vessels. So if you carry on training that guy, you will not improve his aerobic capacity but his performance will still improve, because the lactate threshold is not limited by the cardiovascular system – it’s determined by the quality of the muscles.”

Your body clears lactate from the blood via a series of chemical reactions driven by the mitochondria in your muscle cells. These reactions transform lactate back to glucose again and they are enhanced by specific enzymes. The clearance process also works more efficiently if your mitochondria have a larger capacity, increasing their ability to use lactate as a fuel.

Years of training will improve both your enzymes and mitochondria and so improve your clearance, but there is a limit to how much you can improve your lactate threshold by training alone. If you inherit these enzymes and a larger mass of mitochondria genetically, your personal limits will be far higher.

Karnazes fell in love with running from an early age, and at high school he began to show endurance capabilities which far surpassed those of his peers. At one charity fundraiser, while his fellow runners were able to manage 15 laps of the track at most, Karnazes completed 105. But in his mid-teens he stopped altogether until experiencing an epiphany on his 30th birthday. Gripped by a powerful desire to run once more, he set off into the night.

After 15 years of no training, most of us would not have been physically capable of getting too far, but Karnazes did not stop until 30 miles later. Although the blisters were excruciating, his muscles showed little sign of fatigue.

“Many elite distance runners will show some improvements in their ability to clear lactic acid from the system due to the ‘training effect’, but that only goes so far,” he says. “The rest, as I am told, is left up to heredity. They say the best thing you can do as a long-distance runner is to choose your parents well!”

However, genetics alone does not tell the full story. Karnazes believes that his lactate clearance abilities could also be down to low body fat, low sweat rate, a highly alkaline diet and low exposure to environmental toxins. Genetics can give you the propensity for a natural advantage but you express your genes differently depending on your environment and your lifestyle.

The intriguing question is whether Karnazes’ lactate clearance abilities would be the same now if he had not done so much running at an early age.

“If you take two twins – one grows up in Africa and one grows up in northern Europe – their athletic performance will potentially be very different, because they will express their genes differently as the environment, food, everything is different,” Messonnier says.

An interesting experiment could be to repeat the lactate threshold test with Karnazes’ brother.

“He plays competitive volleyball but has never really done an extensive amount of running,” Karnazes says. “I would be curious if he exhibits some of those same abilities to clear lactic acid from his system.”

Source: http://www.theguardian.com