Artificial Exercise? Scientists Tap Into Endurance
IRA FLATOW, host:
This is Talk of the Nation: Science Friday. I'm Ira Flatow. A bit later, we'll talk about air pollution and the Olympics and a tiny microscope with big power. But up first, finding - a finding here that's very interesting that could be a dream come true for all you couch potatoes. elite athletes and people who, for various medical reasons, cannot work out - I mean, you physically can't get the exercise that you need or you want - a team of researchers found drugs that provide the benefits of exercise without the sweat and the effort, or at least with less sweat and effort. In the laboratory animals that were tested on them, the drugs essentially tricked muscles into thinking that they had exercised.
One boosts the effects of exercise to increase endurance, while the other does the same, minus any effort at all. The researchers say these drugs, if they work in people - and that's a big if - if they work in people as well as they do in mice, could help people with various muscle diseases or other medical conditions that make exercise difficult. And on the other end of the scale, they could be used for abuse. It could be abused by athletes, you know, these elite athletes who want to improve their performance, or any busy person who has a hard time getting a workout and wants to just take the pill instead.
Joining us now to talk about this finding is the lead author of the paper out in the current issue of the journal Cell. Ronald Evans is an investigator with the Howard Hughes Medical Institute. He's also professor and the March of Dimes Chair of molecular and developmental biology at the Salk Institute in La Jolla, California. He joins from the campus of UC San Diego. Welcome to the program, Dr. Evans.
Dr. RONALD EVANS (Investigator, Howard Hughes Medical Institute; Chair, Molecular and Developmental Biology, Salk Institute for Biological Studies): Hi, Ira. I'm delighted to be here.
FLATOW: You're very welcome. I'm always fascinated with the backgrounds of these things, the genesis of it. Give us a bit of a background. You had already genetically engineered mice to be super endurance runners, correct? Like marathon mice?
Dr. EVANS: That is correct. About four years ago, we described the genetic engineering of a strain of mice using a particular gene-regulatory molecule. We call that molecule PPAR-delta. The name is not so much critical, but it's a master regulator of gene control for metabolic genes, and so, this controls metabolism in cells. And we activated that switch genetically in muscles of mice, and the product was a strain of animals we call marathon mice. These are mice that have an uncanny ability to run very long distances without tiring. And that proved to us that there's underlying genetics for endurance that could be understood, and possibly dissected and then manipulated instead of genetically, but with a drug or a pill.
FLATOW: So, you looked for a drug that could turn that switch on.
Dr. EVANS: Well, we knew at the time, since we'd been studying the switch - in fact, had characterized almost 12 years ago - that it was a kind of switch, we call it a receptor, that could be triggered by certain small molecules. And so, our goal after, demonstrating that the switch when thrown could power up endurance, was to find such a molecule that could reproduce that effect in an adult mouse.
FLATOW: And did you find one?
Dr. EVANS: We did. In fact, we found two. And the first of the drugs that we found directly acts on the switch, but unexpectedly, did not increase endurance or running capacity at all until we ask the mice to exercise when we gave the drug. And the combination of exercise and the drug then had a tremendous impact, and that allowed the drug to nearly double the running capacity of the mice, relative to not having the drug. So, it was a big step forward, but it still required exercise.
Dr. EVANS: So, the next step was to actually ask, could we find a drug that might even bypass exercise altogether? And this was yet another big question, do muscles actually have to exercise to improve? And that set us out on the next step of the journey.
FLATOW: And you found a drug that you don't need to exercise with.
Dr. EVANS: Well, in wondering why exercise was required for the first drug, we looked to a component in the muscle that's an energy sensor, a specialized protein that detects, when you're exercising, how to replenish the energy that you're burning. And that is a seamless process. For every bit of energy that you consume, you have to replace it. And there's an energy sensor in the muscle that detects the change, or the depletion of energy, and mobilizes all the forces in the muscle to bring in fat, sugar, power up the small, little chambers called mitochondria, the so-called powerhouse of the cell, to replenish the energy supply.
Dr. EVANS: And our goal was to find a small molecule that could bind to that energy sensor and to trick it into thinking that energy was being depleted, and to activate it, and to stimulate metabolic activity. And that's exactly what happened with one of the drugs that we describe in our study.
FLATOW: So, you trick it into thinking that it has been exercising when it hasn't been exercising.
Dr. EVANS: Exactly. The sensor doesn't really know if true exercise has occurred or whether it's the drug that's activating this enzyme. And exercise and the drug power up this enzyme approximately with equal efficiency, leading us to speculate that perhaps the drug alone could, in a sense, deceive or trick the muscle into believing it had really been exercised, but without having done any exercise at all.
FLATOW: And as something does get exercised, your endurance goes up. So, you tricked it into thinking - you created more endurance in the animal.
Dr. EVANS: And that was the surprising result we had.
(Soundbite of laughter)
Dr. EVANS: I honestly wasn't sure that it was possible to package exercise in a pill, because exercise is such a complicated series of steps of mechanics...
Dr. EVANS: And nerve activation of the muscle, and calcium influx, many things that happen and stretch. And of course, this was not happening in these animals. It was a very passive effect both on the genome and on the metabolic activity in the cell. But otherwise, it's passive. Yet after 20 doses or 20 days of treatment with this drug, the animals behaved as if they had received 20 days of exercise. And they got on the treadmill and ran 44 percent farther than mice that did not get the pill.
FLATOW: Wow, wow. Do you suspect this would work at people if it works in mice?
Dr. EVANS: That's a very good question. First, we were stunned that it works in mice. But the good news is that the exact same pathways that these drugs are flickering on in the mouse are present in the human. Now, that doesn't mean that all the human biology and the mouse biology will be the same. But it's very clear that it's likely that these drugs are going to trigger some effect in muscle. The question is, can we find the right form of the drug, or the right dosing ,to reproduce the effects that we have in these sort of couch-potato mice?
FLATOW: You know, with the Olympics in Beijing starting next week, there's always the thoughts of doping, you know, chemical doping, taking drugs. This would seem like a perfect kind of problem for this kind of drug.
Dr. EVANS: I would say that the Olympics raise the classic dilemma of how one develops a new drug that has, in this case, potential to increase performance directed towards people who need that boost, but the first users may, indeed, be competitive athletes whose career is based on performance, and they are willing to try drugs before they're actually approved.
FLATOW: Can you make a test for it?
Dr. EVANS: That's a very good question. Realizing full well that the athletic community may begin tinkering or experimenting with these compounds in a very early fashion, we already developed a highly sensitive, very quantitative blood-and-urine test for these molecules and their metabolites. And that test and the protocols for its implementation have been passed on to the World Anti-Doping Association, or WADA, and they're in possession of that. And I think that they're told us they have it, and they will not tell anyone specifically when or where they will deploy it, because they don't want people to know when it's going to be used or how to avoid it, but they have it.
FLATOW: Right. In the couple of minutes I have left, Dr. Evans, let's talk about the more practical uses for everyday life for this kind of medication.
Dr. EVANS: Well, you may wonder why exercise and a pill, and of course, we're not trying to tell people they shouldn't exercise, or that they should get rid of their passes to the gym, but rather there are a large group of people who either cannot exercise for reasons, for example, hospitalization, surgery. I've had many people write to me about back pain, leg surgery, people who are in wheelchairs, and these individuals are in desperate need of some form of exercise although they can't perform it themselves. And so, that's one group. The elderly who are frail also could potentially benefit from a drug that stimulates exercise, and possibly kids with muscular dystrophy, who also have many problems. Then there's the larger group of people who are overweight, who just do not have endurance, and could use a pill that promotes endurance to jump-start their own problematic physiology.
FLATOW: Yeah. This doesn't make you stronger, this pill. It just is endurance. It's not going to create larger muscle mass in case you need to be stronger, correct?
Dr. EVANS: This pill is not like an anabolic steroid.
Dr. EVANS: Which creates strength. Rather, exactly what you said, it increases endurance, which has not been possible with a pill or a drug previously.
FLATOW: And if having such endurance you might then be able to increase your strength by doing an exercise program, whereas you might not have been able to do that before.
Dr. EVANS: I think that's a very good point, and we certainly know that endurance runners, or cyclists, or swimmers, are in exceptionally good shape, in great cardiovascular systems, and have increased resistance to a lot of disease. So, something that could promote endurance, I think, would be a very interesting compound to bring forward.
FLATOW: All right, Dr. Evans. Thank you very much for taking time to be with us.
Dr. EVANS: Delighted to be here.
FLATOW: And good luck to you. I'm sure you've been deluged with requests.
(Soundbite of laughter)
Dr. EVANS: I have been deluged with requests from a remarkable cross-group of people.
FLATOW: Yeah. Well, fend them off the best you can, but thank you very much.
(Soundbite of laughter)
Dr. EVANS: All right, thanks a lot.
FLATOW: You're welcome. Ronald Evans is an investigator with the Howard Hughes Medical Institute, and professor and chair of molecular and developmental biology at the Salk Institute for Biological Studies in La Jolla, California.
We're going to take a short break and come back and talk about the Olympics. We've mentioned the Olympics. They're up next. Our man, or our woman, in Beijing - as they used to say in an old novel - will be with us to talk about the air pollution. So, stay with us. We'll be right back.
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FLATOW: I'm Ira Flatow. This is Talk of the Nation: Science Friday from NPR News.