Exercise in a Pill?

Steven R. Smith, MD; Daniel P. Kelly, MD

Disclosures

December 27, 2011

Editorial Collaboration

Medscape &

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Steven R. Smith, MD: Hello. I'm Dr. Stephen Smith, Professor at the Sanford-Burnham Medical Research Institute. Welcome to this segment of Developments to Watch from Sanford-Burnham and Medscape.

Joining me today is my colleague, Dr. Daniel Kelly, Director of the Diabetes and Obesity Research Center and a cardiologist. Today's program will focus on key research addressing the links between exercise, obesity, and diabetes as well as the detraining and retraining of muscle cells that are weakened by obesity and other chronic conditions. Importantly, we'll discuss how this research will affect clinical practice. Thank you for joining us, Dan.

Daniel P. Kelly, MD: Thank you for having me. I'm delighted to be here.

Dr. Smith: There's an obesity epidemic in the United States right now. Tell us a little bit about how that influences insulin resistance and muscle in particular.

Dr. Kelly: As you mentioned, we are really experiencing a world health crisis in obesity that is driving all types of morbidities and problems -- diabetes being the primary one, but a number of other problems in many organ systems.[1]

When you look at the general condition and physical conditioning activity and stamina as well as general activity and muscle of these patients, we and others have found that there are very significant changes that lead to what we refer to as a vicious cycle.[2] The musculature, as you know, requires daily activity. Training exercise itself enhances the performance of the muscle. It also improves its ability to use glucose, makes it more insulin sensitive -- the opposite of type 2 diabetes -- burns calories, and in some studies actually reduces the onset of many of the morbidities associated with aging itself such as musculoskeletal problems and even cognitive function in some studies.[3,4]

When we think about what happens to the muscle in obesity and in diabetes, it's good to think about how often these individuals are able to have activity in the right way. What happens, as you know, is that the degree of daily activity begins to decrease with obesity. In addition, we now see that the obesity itself seems to affect the function of the muscle, creating this vicious cycle, such that the muscle no longer works as well -- less activity, less calorie burning, and more obesity creating this cycle, which ultimately leads to insulin resistance. There are a number of studies going on around the world aimed at the metabolic and structural changes that occur in the muscle in the very early stages of insulin resistance caused by obesity.[5]

Dr. Smith: So, Dan, this vicious cycle that occurs -- tell us a little bit more about that. The muscle seems like it's not working properly, but what's the other half of the cycle? How does that work?

Dr. Kelly: There are a couple of things that we know about the muscle in the obese and diabetic state. When you think about the components that have profound exercise tolerance in, for example, elite athletes, many of the attributes and muscle components are the same things that seem to go backwards and become deactivated in the obese state.

For instance, the skeletal muscle fibers are referred to as fast and slow fibers. The endurance fibers, the slow fibers, have, for a long time, been recognized as markers of fit muscle. In the obese state, there is a shift away from those fibers.[6] Another important component is the mitochondria. The energy power-house of the cell is very important in muscle, and, with fit conditions or exercise training, the mitochondria expand and allow the muscle to be able to use fuels, both glucose and fatty acids, in very high-capacity ways. In the obese state and in the diabetic state, it moves in reverse, so that the mitochondria are not working as well.[7]

In addition, the vasculature itself for the muscle expands with training. In the fit individual, the vasculature is plentiful in the muscle; in the obese and insulin-resistant states, we see a regression, if you will, a relative insufficiency, of the vasculature.[8]

So when you put all of this together, it's almost as if these individuals have been inactive or immobilized for a long period of time, but indeed that's not the case. There's just a modest reduction in their activity. So, as you suggested, there seems to be another component, the obesity component.

Studies recently have suggested that what actually happens is that, with expansion of the adipose tissue, which holds on to all of these excess calories as fat, there is a point at which the fat tissue is no longer able to hold on to all of those excess calories. Out they go as fatty acids either from the fat tissue through lipolysis or put out from the liver itself in the form of lipoprotein particles that are triglyceride-rich. Some of this fat ends up in muscle tissue.[9]

So when we begin to look at the skeletal muscle of the early insulin-resistant individual en route to developing diabetes, we actually see accumulation of fat in the muscle cell. This was, I think, one of the first clues that part of this detraining effect might actually be due to so-called lipotoxicity in the muscle.

Dr. Smith: There has been a lot of work on this detraining effect, the mitochondrial defects that you've mentioned, this inability to burn fat. Much of that has come from your lab. You've had some recent advances in this area. Tell us a little bit about how this occurs and what those systems are that control this detraining vicious cycle response.

Dr. Kelly: These studies actually began in kind of a reductionist approach, simply asking the question: if we could find the factors that maintain high mitochondrial number in the muscle, would that be enough to take care of much of this problem?

These were done in genetically modified mouse studies. We and others have identified a factor called PGC-1, which boosts the activity of a number of different nuclear hormone receptors in the muscle. We and others had shown that this booster increases the number of mitochondria in the muscle cell.[10] We wondered: if simply by activating this particular circuit, could we block some of the myriad problems that occur leading to the detraining effect, similar to what happens in obesity? Also, could we mimic the effects of obesity in muscle by not having obesity so we could prove that this was the problem?

So, as we tend to do in the laboratory, we did what we call gain-of-function and loss-of-function studies. In one case, we would overexpress this factor, PGC-1, in the muscle.[11] When we and other people in the field did this, we ended up having marathon mice. These mice could run longer than normal mice and would run and run and run on the treadmills. You'd almost have to pull them off they liked to run so much. When we looked at the muscle, it had not only more mitochondria, but many of the different features of the trained state that I mentioned before, like this fiber shift to a more enduring fiber and more blood vessels.[12] This meant that PGC-1 was somehow talking to many other networks and showed great promise, actually, for a new therapeutic target, if you will, exercise in a pill.

On the other side of the coin, if we were to take the PGC out, we wanted to see -- and that was done by genetic manipulation -- we wanted to see if these mice looked more like the obese state. Sure enough, these animals would hardly run at all on the treadmill compared with their normal counterparts.[13] They'd run for a few minutes while the other ones would run for hours. They did not get obese, so we had kind of uncoupled the obesity from this, but for all the world they looked like couch potato mice. So these types of studies have suggested that this circuitry might be a reasonable target for new therapies that would enhance muscle fitness.

Dr. Smith: So Dr. Kelly, that's really exciting. Is this going to replace exercise? We won't need to go to the gym or go for walks in the evening. Tell us, is that where we're going?

Dr. Kelly: This question comes up quite a bit, as you might imagine. No, actually, we don't think there's any real replacement for exercise. On the other hand, getting back to the vicious cycle, if we could break the vicious cycle, for example, try to stop whatever happens in the muscle to create detraining in the obese state -- possibly related to this lipotoxicity -- it might allow these individuals to begin exercise training programs or even get out and do things and lower the threshold obstacles to starting.

We also believe that if you could develop such therapies, it would have implications not only for the obese population but also for those who are recovering from an injury, for instance. This would even include soldiers in combat who are at very high training states but are prone to have injuries and then go back and believe they can perform at the previous level but certainly cannot and so they reinjure themselves. You could envision a number of scenarios where this type of so-called exercise-in-a-pill therapy would promote exercise and break the vicious cycle, but we doubt whether you'd simply be able to completely replace all of the beneficial effects of exercise on bone, muscle, cognitive function, and what have you.

Dr. Smith: This is an exciting area of research, Dan. The ability to develop these new therapies -- what does that pathway look like into the future and what does our timeline look like for some of these developments?

Dr. Kelly: Great question. These are early studies. They're in preclinical scenarios. The way that we think about doing this is several-fold.

One is through what we call a candidate approach. I've just mentioned a candidate, the PGC factors, or many of the various factors downstream of PGC-1. The usual scenario, and one that we take at the Sanford-Burnham Medical Research Institute, is to bring in teams of scientists that begin to look at whether any of those molecules could actually be drug targets and then to conduct what we call small molecule screens, or robotic screens, screening hundreds of thousands of compounds to see if any of them would activate either the upstream factor PGC-1 or downstream. If any of these turn out to be druggable, then we're on our way. Usually this results in a partnership between academia and industry for drug development, validation, and more studies. So we're talking about a number of years, but at least we have a lead.

The second approach, however, we're also very enthused about. It's a little more risky, but we think it shows great promise for developing a pipeline of such agents. As I mentioned before, we think that the real culprit here is the accumulation of fat in the muscle cell. So we've been thinking about ways to take muscle cells and put them in culture and load them with fat and, again, screen molecules or even genes to see if any of those molecules or genes are able to reduce the amount of fat in a muscle by burning it away. At the same time, if they are able to do that, we look to see whether they increase mitochondria and other signatures of training.

We'd run both of those strategies in parallel in order to identify new targets for new drug therapies. This would be aimed at the broad expanse of the obese population at risk for insulin resistance and diabetes, and maybe even for those where the insulin resistance and diabetes had already ensued.

Dr. Smith: So these new therapeutic targets could produce drugs that could be used in a variety of different disease states. You mentioned some of these -- obesity, to get people activated and energized for being able to exercise, all the way to detraining after surgery and these sorts of things. Tell us about some of the other indications for which the exercise in a pill might be useful.

Dr. Kelly: This is another fantastic question, and it's something that we talk about quite a bit. The sky is really the limit when you start thinking about muscular disorders.

Right now, we are facing a very high-volume problem in obesity and diabetes, but if you think about some of the other types of conditions, aging itself causes problems in muscle. It's interesting that some individuals seem to have the aging process hastened in the muscle for whatever reason. There are a number of genetic disorders, such as muscular dystrophies, that may end up benefitting from activating the training response in muscle.

I had mentioned a little bit about soldiers in combat and other detraining scenarios, and one of the really interesting scenarios to think about is the loss of gravity, the microgravity effect that one would experience during space travel. Obviously, we're not at that point right now, but it is, of course, still envisioned that, either for research purposes or ultimately for other types of purposes, there will be quite a bit of space travel, and one of the big problems has been a detraining effect in muscle.

As you've mentioned, recovering from injuries or even the chronic illnesses such as cancer, where the cachexia of cancer also results in very significant muscle problems.

Dr. Smith: But all of these approaches would target the muscle, right? Is this a muscle-specific therapeutic approach, or are there other organs? How do you see this? Is it muscle-specific or are we looking at other mechanisms as well?

Dr. Kelly: I'm glad you asked that because we've started with muscle for many of these studies, but, as you know, we're very interested in the heart and other organ systems. We have begun to take some of our positive findings in skeletal muscle and move, for example, to the heart. In many cases, the heart has benefitted from the therapies that we've identified, the potential therapies --

Dr. Smith: So it's like exercise-training the heart then? It's the same idea.

Dr. Kelly: Exactly. I should mention that the fat accumulation that we see in muscle is also true in the heart in the obese and diabetic population,[14] so whether we call it detraining or whether we call it heart failure, we would really like to come up with a therapy that would hit multiple organ systems, burn away fat, and enhance function.

Dr. Smith: So what are the next steps? What can clinicians look for in the next couple of years? Tell us where we should be paying attention, particularly in terms of the literature for this kind of work.

Dr. Kelly: We should look for additional proof-of-concept studies in humans. A number of studies have shown a correlation between lipid accumulation and mitochondrial dysfunction in muscle and insulin resistance. Indeed, work has been done by a variety of different scientists, and physician scientists have indicated that the mitochondrial dysfunction and the fat accumulation has its own vicious cycle.[2] So the clinicians should look for studies that will be popping up in humans for more proof of concept that when lipid accumulates, mitochondrial dysfunction occurs. This will be done with very sophisticated spectroscopy approaches and others looking at mitochondrial function at the same time that it's monitoring accumulation of lipid and skeletal muscle.

After those types of studies, or in conjunction with those types of studies, there will be studies aimed at intervention on the lipid itself to see if, when it's reduced and burned away, we see an enhancement of mitochondrial function and skeletal muscle function in general. Again, we have some of those early studies in the literature,[15] but I would anticipate that there will be many different kinds of approaches in this regard -- some approaches directed at the skeletal muscle and some approaches directed at other tissues to pull the fat away.

Dr. Smith: It's a very interesting topic, Dr. Kelly. Thank you for being here today and participating in this program.

We would both like to thank you for joining us today. I hope you will join us for additional programs in the Developments to Watch series on Medscape.

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