Transcript

Keith Baar, PhD: Hi there, I’m Professor Keith Barr. I’m a professor of molecular exercise physiology at the University of California Davis, and my colleague here is Henning Langer.

Henning Langer, PhD: And I am a biologist focusing on skin and muscle wasting at the Charité Berlin. And we are particularly interested in the effect of GLP-1 medicines and their effect on skin and muscle.

Keith Baar, PhD: Perfect, and so our latest study showed that GLP-1 therapy leads to improved body composition without any real negative effects on either muscle mass or strength, both in mice and in humans. Can you kind of talk about what you think is going on here as far as maintaining the functionality, even though we’re losing muscle mass?

Henning Langer, PhD: Yeah, sure, thanks for that question, Keith. I think the thing that spurred the question for accelerated muscle wasting with GLP-1s was the step one trial, which was simultaneously the trial that got semaglutide approval as an anti-obesity medication. Because in that trial they found that in a subpopulation that was analyzed for body composition via a DEXA, which is dual X-ray absorptiometry, they saw that there was around 40% of contribution of lean body mass or fat-free mass to the total body weight loss, which is a little bit more than what you would usually anticipate with traditional lifestyle intervention and physiological weight loss, where the quarter fat-free mass rule would predict that it’s only around 25% of the weight loss that’s due to a decrease in lean body mass. So, you know, we were concerned that maybe there’s something disproportionate about GLP-1 signaling in specific manner to skin and muscle that would explain why maybe there’s this huge portion of lean mass being lost.

Keith Baar, PhD: Right, so you didn’t find that though. We didn’t find that in the group. So what did we find?

Henning Langer, PhD: So we saw that actually, you know, the lean mass loss was still significant in absolute terms, but if you compare it to how much fat mass was being lost, you know, the lean body mass made up a quite small margin. And similarly for skin muscle specifically, and that’s something that wasn’t really explored in much detail previously in the literature. So we looked at that in the preclinical, but also, you know, in a clinical situation and especially in mice, we found that actually the decrease in muscle mass in absolute terms is still slightly significant. It’s a small, very modest decrease, but in relative terms, meaning how much muscle mass there are still being left compared to the total body weight of the animals, relative muscle mass actually went up. And similarly, for muscle function, we also saw that absolute strength went down a little bit when you look at it, but in terms of how well these animals performed on the treadmill, for example, they were running much better, much faster, much longer than their obese counterparts. So we think that, yes, there is an absolute decrease in muscle mass, but there doesn’t seem to be anything that’s disproportionate per se. We think this is mostly a function of the body weight loss.

Keith Baar, PhD: So we always lose muscle when we lose mass. So we lose about a quarter of the mass that comes off if we’re not taking in a sufficient number of calories, a quarter of what we’re losing is normally coming from our muscle when we’re not doing anything to prevent that. So I know that you just finished your exercise bout here, so why don’t you just quickly, you know, hypothesize as to what would happen, or other ways that we can actually minimize that 25% muscle loss.

Henning Langer, PhD: Right, so there is huge interest in the pharmacological community and the drug development community about developing compounds that could maintain muscle mass in situations of wasting, even if it’s just, you know, basically physiological decrease in muscle mass due to decrease in body weight. But we also have sarcopenia and cachexia and other situations where that drug could also be of benefit. But in terms of lifestyle interventions that are available, we know from many, many clinical trials that, especially resistance exercise, is able to decrease the lost lean body mass by around 50%. So basically you go from 25% to something in the neighborhood of 10 to 15% contribution of lean body mass. If you then combine that with high protein intake, you go even lower and you can minimize the decrease in lean body mass to, you know, almost a negligible amount.

Keith Baar, PhD: So you can be still losing fat mass even though you’re, and you will still lose muscle mass. There’s nothing we can do about that when we’re not taking in a sufficient number of calories. But by doing resistance exercise and by adding in some protein, most people nowadays though don’t really need to add extra protein because that is something where the supplement companies have been so good that everybody is all focused on protein. But having that extra protein about, say about 0.4 grams per kilogram body weight at every meal that we wanna have when we’re losing weight, that’s gonna help us to maintain as much muscle as we can.

So then in the clinical portion of the study, basically the team directly looked at muscle strength and this is something that most, well, none of the other GLP-1 studies have looked at. And really what did you see as the key implications for what you’ve found in that, and how does that kind of lead us forward into any kind of obesity drug research as to what might be really important that everybody has for clinical trials in this area moving forward?

Henning Langer, PhD: Yeah, so to be fair and upfront, we did not do that in a large cohort that, you know, would allow us to have permanent conclusions in that direction. But we did do a nice pilot trial in collaboration with the University of Nottingham and the lab of Phil Atherton and Iskandar Idris, and they recruited patients that were diabetic and obese and apply semaglutide for 12 weeks. And they did, and that is, like you said, one of the first times that they actually directly looked at changes in muscle function, they actually did maximum voluntary contraction of the knee, meaning that they did leg extensions and measured how much force the patients could exhibit rather than just looking at hand grip strength. We also looked at hand grip strength, but as in so many other trials, we didn’t really see anything changing. So we think that, and I think most muscle physiologists would agree with me, that the direct measurement of force through the maximum voluntary contraction of the quadriceps is probably more telling about how much strength these patients still retain. And we found that there wasn’t really any meaningful decrease, neither in absolute nor in relative terms, it just didn’t really change all that much. And there’s a possibility that it would over the long term. But we also know from those large scale clinical trials, even though they didn’t directly look at it, they still surveyed how functionality of these patients developed over the course of the trial. And actually the patients that had the worst baseline, self-reported physical function, benefited the most from the weight loss. So even those that are, you know, borderline frail, or have very bad physical function, if they lose a substantial amount of weight, they still seem to be doing better if they lose, you know, GLP-1 induced body weight.

Keith Baar, PhD: Yeah, exactly, this is ancient in how it works. The Sherpas used to do this when they would get tired. When they would get tired, they’d put lots of rocks into their pack, and that’s kind of not what you’d expect. But then what they’d do is they’d walk for a while, they’d take the rocks out and they’d feel really light and it’d be easy. And so they know that when they do that, when they take off the extra weight, it’s gonna feel so much easier to do the work that it actually helps them in the long run. So, again, I think all of these things are really important for this idea that that when we’re looking at kind of anything to do with losing mass or anything to do with muscle, that it’s really important to look at strength. And then the number one reason is that we actually lose strength about three times faster than we lose muscle mass. And so it’s a really important thing that when we are losing strength, that we know about it because that’s gonna be the thing that’s really important for long term health and longevity. So in these older populations especially, it’s really important to look not only at strength, but to look at leg strength because we are bipedal, so we need to move on our legs, we need to be able to get up and move around, and that’s gonna really tell us how functional we are.

Henning Langer, PhD: Yeah, and I agree, I think there is a lot to still be explored in a geriatric context. So we are specifically interested in the effect of aging in conjunction with GLP-1 medicines and what that does to skin and muscle because there is this point in life where having a low body weight and a lower BMI epidemiologically very well proven is actually detrimental to life expectancy and quality of life in these things. And so, unless you are very, very obese, meaning, you know, a BMI of beyond 33, 35, you probably have to be a little bit careful about weight loss in general, whether that is GLP-1 induced or lifestyle induced because beyond the age of 65, 70 and beyond, the possibility of a little bit of extra reserve, not just skin and muscle but actually also fat, is something that could help prevent things, like sarcopenia, cachexia and so on.

Keith Baar, PhD: Yeah, exactly, you and I both know that being big when you’re younger isn’t great for your longevity, but being big when you’re older is much, much better.