The Science Behind ‘Hitting The Wall’

12:01 minutes

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If you’ve ever watched a marathon, you’ve probably seen runners near the end of the course collapse to the ground in exhaustion. This is known as “hitting the wall.” In a study out this week in Cell Metabolism, scientists studied the genetic and metabolic mechanisms that leads to this exhaustion in mice.

[Diet pill mimics the effects of eating.]

It’s been shown that running can trigger a gene called PPARD. In this recent study, researchers were able to flip a switch along a pathway of gene expression that increased the running endurance of mice by 70 percent. Ronald Evans, an author on the paper, talks about what this research suggests about how the body builds up endurance and consumes glucose and fat reserves during exercise.

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Segment Guests

Ronald Evans

Ronald Evans is professor and director at the Gene Expression Laboratory at the Salk Institute and investigator at the Howard Hughes Medical Institute in La Jolla, California.

Segment Transcript

FLORA LICHTMAN: This is Science Friday. I’m Flora Lichtman. Ira Flatow is away. Later in the hour, we’ll be talking about a post-apocalyptic world ruled by threatening biotech. That’s from Jeff VanderMeer new novel Borne.

Do you want to talk about your favorite apocalypse scenario? Then give us a call. Our number is (844) 724-8255. That’s (844) SCI-TALK, or tweet us @scifri.

But first, new research into a chemical compound that increases endurance without actually having to exercise, at least if you’re a mouse. Reporting this week in the journal Cell Metabolism, scientists flipped a particular genetic switch in mice. And the mice ran 70% longer, 70% longer, than control mice, without any physical training. So what does this mean for your workout? Can we all say goodbye to our pump-up playlists?

Let me introduce my next guest. Ronald Evans is an author in that study he’s also an investigator at the Howard Hughes Medical Institute, and a professor and director of the Gene Expression Laboratory at the Salk Institute in La Jolla, California. Welcome back to Science Friday, Dr. Evans.

RONALD EVANS: Thank you. A great pleasure to be with you.

FLORA LICHTMAN: So, Dr. Evans, one of the things that I thought was so fascinating about this study is that we actually have a gene pathway at all for endurance. Is that true?

RONALD EVANS: Yes. I mean, we do have a gene pathway for endurance. And that’s really what a large part of the study is to try to understand.

FLORA LICHTMAN: How many genes are in it?

RONALD EVANS: It’s not a specific number, although we do describe the genes that we see. It’s minimally several hundreds of genes. And it’s probably a few more that get dialed in with parallel pathways, depending on what you call “exercise.”

So “exercise” is a term that does not actually express something specific, other than a process of what you do leads to better performance of what you’ve been doing. But walking can be exercise for some people, a fast walk can be exercise for others. But it might not be good exercise for a Lance Armstrong-type person. And so yoga for some people is exercise.

But at the performance level of endurance athletes, then they’re taking exercise to the human physical limit, for example. And so there’s a whole range of what you might call exercise. And the underlying feature is that we all plug into the same genetic pathway.

And I think one thing for the listener is that exercise, as soon as you do that mechanically, activates a set of genes in your muscle. That’s very important. And so the fact that that happened means that, if we understand what is the controller of that gene network, then we might be able to actually hit that controller, that master regulator.

FLORA LICHTMAN: And that’s exactly what you found. The controller for that.

RONALD EVANS: That’s exactly what we found. Exactly

FLORA LICHTMAN: Yeah. So how do we hack into it? What did you do.

RONALD EVANS: Well, the nature of the hacking was not simple, actually. Because when you want to hack the genome, it’s like you need the right algorithm to access the set of genes that are normally not being activated. And the master, really the ringmaster, of this is a type of molecular software we call PPAR delta.

FLORA LICHTMAN: That’s very catchy.

RONALD EVANS: It’s the name of it. I know, it’s not a great name. But it is a sensor for fat, and it lies in the nucleus of the muscle cell. And when fat is pouring in to burn as energy, some of that goes in and hits the sensor. And the sensor actually has a set of algorithms that reprograms the hardware of the genome to marshal up the genes that are needed to burn fat. So the secret–

FLORA LICHTMAN: So this is how it happens when you’re actually exercising?

RONALD EVANS: It’s what’s happening when you’re actually exercising.


RONALD EVANS: And we discovered this sensor, actually embarrassingly, in some ways, back in 1995. This is the arch of when we didn’t know what it did, but we discovered it.

And it turns out it is the master regulator of this pathway. And because it likes to bind fat, and that’s what turns it on, and that it, in turn, plugs into the gene network, and is the coding for the activity of those genes, those exercise genes, we developed a drug that mimics fat, but is not fat the chemical. And it gets into the body. It’s orally active and–

FLORA LICHTMAN: So you can take it? You can take a pill or something?

RONALD EVANS: If you take this pill, finds the sensor, and uses that to activate the genes without any exercise.

FLORA LICHTMAN: And what does it actually do. Like, how does it make these mice have greater endurance?

RONALD EVANS: Well, so there’s two things that happen. And that’s the great question that we are addressing is, a little bit, what is endurance? Number one, it’s actually not what people think it is from a scientific point of view. And–

FLORA LICHTMAN: I think that as being able to exercise longer.

RONALD EVANS: Yes. But training progressively allows you to run. Let’s say you’re running or cycling, or swimming or doing some kind of endurance challenge. The training will progressively and incrementally increase your ability to do it longer. If you or I– Are you a runner?

FLORA LICHTMAN: In the past. I have been.

RONALD EVANS: Because runners know that if you just get up and start running, you’re going to hit the wall relatively soon.

FLORA LICHTMAN: I can testify to that.

RONALD EVANS: You will poop out. And part of the paper and, really, the big scientific underpinning of this paper is what is hitting the wall? And this is the event that terminates their run or race or the cycling for athletes.

You see it happen all the time in the Tour de France, when even lead athletes will hit the wall and they just drop to the back. You cannot overcome that process in any simple way when it happens. And we’re trying to understand that, because endurance is progressively moving the wall to make it not be in your way. And as you move the wall–

FLORA LICHTMAN: It’s not scaling the wall. It’s pushing the wall back.

RONALD EVANS: It’s not scaling the wall. It’s not scaling a wall. And this wall, Mexico’s not paying for this wall. But the point is that when you hit the wall, you become disoriented, and you’re overtaken by sudden and overwhelming fatigue. Often dizzy, and your race is basically over.

FLORA LICHTMAN: So does this gene pathway help you move the wall.

RONALD EVANS: Yes. So this is the pathway that actually helps you move the wall. And what we found is that endurance and all the training that you do is really about moving the wall. And so then we said, what is the wall? And so the wall is actually a sugar wall.

And that’s part of the interesting science. It’s long been known that if you deplete your blood sugar, by any means, below something like 70 milligrams per deciliter, you become what’s called hypoglycemic. That is low blood sugar. The brain only lives off sugar. That’s how it keeps going.

Muscle can burn sugar and fat. So muscle has two sources of energy, but the brain only has one. If you’re going to burn a lot of energy over a long period of time, you have to have your brain staying along with your muscle. And because the brain only burns sugar, progressively to move the wall, that is, to allow your brain to keep going–

FLORA LICHTMAN: You have to burn more fat.

RONALD EVANS: You have to burn more fat and burn less sugar. The less sugar you burn in the muscle, the more there is for the brain. The more you give to the brain, the longer you can run.

FLORA LICHTMAN: So does this gene pathway let you burn more fat in your muscles?

RONALD EVANS: So it lets you burn more fats. And one of the big benefits, it lowers your lipids in your blood. It burns fat from your adipose depot. You know that long distance runners and cyclists tend to be skinny because they have very little fat. And so it transitions the energy stores in your body, which you were using the stored energy in the body to both drive muscle and to keep the brain going.

But the point is how you shift the ratio of the usage of the nutrients, in the right way, is the secret to moving that wall and gaining the endurance. And the surprise of the science here is that the longer the brain stays active, the longer you will be able to run. And so it’s more about the brain and sugar than we previously thought.

And we described the actual genes in the events that go on that preserve the sugar. And through that, there’s a specific set of events that happen. Sugar gets burned in athletes in a–

FLORA LICHTMAN: I think what people are going to really want to know is can they take a pill that will activate this pathway and let them burn more fat while they’re exercising, and get past the wall? Like, is that what’s coming next?

RONALD EVANS: Yeah. So I would say that’s a good question. That is what’s coming next. And so while the study here was with mice. And the mice, remarkably sedentary mice, that received the drug that we use improved their performance by 70%, which is a very big number.


RONALD EVANS: It’s huge. The goal is now quickly transition this into people. And there’s actually a company in Boston that is taking this on. They’re called Mitobridge. And I do consult with them, just to be clear. And they’ve developed a new form of the pill for people, as opposed to one that we used for mice.

FLORA LICHTMAN: I heard there are some side effects to the chemical used for mice.

RONALD EVANS: So the chemical for mice is not a good drug for people. We call it a dirty drug. On the other hand, the country of Russia actually built a center and made this drug, and gave it to their athletes, has been giving it to their athletes, based on our work, for some time. And the two things that we learned from that–

FLORA LICHTMAN: And we have about 20 seconds, just so you know

RONALD EVANS: –is that it does improve performance. But it’s also not safe. So the safe drug has now been formulated. It’s in a pill form and should be going to trials relatively soon. So we’re very excited by that.

FLORA LICHTMAN: That’s really fascinating. Thanks for joining us today.

RONALD EVANS: My pleasure. Thank you.

FLORA LICHTMAN: Ronald Evans is an investigator at the Howard Hughes Medical Institute, and a professor and director of the Gene Expression Laboratory at the Salk Institute in La Jolla California.

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