Unlocking Muscle Growth: Scientists Pinpoint Key Regulators in Postmenopausal Women

Okay, let’s talk about muscle. You know, that stuff that keeps us strong, helps us move, and frankly, just makes us feel capable. As we get older, especially after menopause, keeping that muscle mass can feel like an uphill battle, right? It’s not just about looking toned; it’s crucial for our health, metabolism, and overall independence.

I mean, think about it from an evolutionary perspective. For most of human history, food was scarce. Our bodies got really good at saving energy. And guess what’s an energy hog? Muscle! So, over time, we developed internal systems that actually *limit* how much muscle we build, just to conserve those precious calories. It made sense back then.

Our Ancestors Were Built Differently

Fast forward to today. We’re often dealing with the opposite problem: too many calories and not enough movement. Those same energy-saving mechanisms that limit muscle growth now work *against* us, contributing to things like weight gain and sarcopenia – that age-related muscle loss that can really impact our quality of life.

Scientists have known for a while that a protein called GDF8, also known as myostatin, is a major player in putting the brakes on muscle growth. It acts through specific receptors in our muscles (called ActRIIA/B). Naturally, folks started thinking, “Hey, if we block GDF8, maybe we can boost muscle!” And they were right, to an extent. Blocking GDF8 *does* help.

But here’s the twist: blocking the *receptors* (ActRIIA/B) seemed to have an even *bigger* effect on muscle growth than just blocking GDF8 alone. This suggested there were *other* signals hitting those same receptors, also telling our muscles to chill out. We suspected another protein, Activin A (ActA), was the key second culprit. Studies in animals (mice and monkeys) backed this up – blocking both GDF8 and ActA together looked a lot like blocking the receptor itself.

Putting the Brakes to the Test

So, we wanted to see if this held true for humans. Specifically, we focused on healthy postmenopausal women in this Phase 1 trial. Why postmenopausal women? Well, initially, there were some preclinical safety concerns about ActA blockade affecting reproductive function, so we started with a population where that wasn’t an issue. (Later, we included some men too, once those concerns were eased by further studies).

This wasn’t a huge trial – Phase 1 trials are mainly about safety and getting a first look at how a drug works in people. We had 82 volunteers in New Zealand. They were healthy, within a certain age and BMI range, and agreed to keep their diet and exercise habits the same (super important so we could see the drug’s effect, not just lifestyle changes!).

We tested different scenarios: giving an antibody to block GDF8 alone, an antibody to block ActA alone, a combination of both antibodies at different doses, or just a placebo (a dummy treatment). Some participants got a single dose, others got multiple doses over several weeks.

Our top priority was safety – checking for any adverse events. But we also measured changes in body composition using fancy tech like MRI (for super-accurate thigh muscle volume) and DXA (for total lean mass, fat mass, etc.). We also tracked how the antibodies behaved in the body (pharmacokinetics) and how they affected the levels of GDF8 and ActA (pharmacodynamics).

The Dynamic Duo Delivers

And guess what we found? In the postmenopausal women, blocking both GDF8 and ActA together led to significantly *greater* increases in muscle mass compared to blocking either one alone, or compared to placebo. It wasn’t just a small bump; we saw substantial, dose-dependent increases in thigh muscle volume measured by MRI.

Not only did muscle go up, but fat mass tended to go down. This makes sense – more muscle burns more energy, even at rest, which can help reduce fat over time. We saw these positive changes in measures like total lean mass and appendicular lean mass (that’s lean stuff in your arms and legs) using DXA, and corresponding decreases in android fat mass (belly fat) and total fat mass. The combination treatment, especially at higher doses, showed the most consistent and statistically significant benefits across these measures.

Seeing the Effects Stick (and Then Fade)

We also looked at multiple doses. Giving the combination treatment repeatedly continued to show increased thigh muscle volume. However, when treatment stopped, the muscle size gradually returned to baseline by about week 28. This tells us that GDF8 and ActA are constantly working to regulate muscle, and you need to keep blocking them to maintain the increased muscle mass. It’s like taking your foot off the brake – the car slows down again.

We also checked out the pharmacokinetics – how long the antibodies stayed in the system. The effects on muscle and fat seemed to mirror the levels of the antibodies and the resulting changes in total GDF8 and ActA levels in the blood. When antibody levels were high and the ligands were blocked, muscle increased. As the antibodies cleared, the effects faded.

What about the men in the study? They only received the ActA antibody alone (not the combination in this specific trial part). We didn’t see obvious changes in muscle or fat mass in this small group, which wasn’t surprising given the primary focus was safety and the limited sample size for efficacy in this cohort.

Keeping an Eye on Things: Safety First

So, was it safe? Generally, yes. The antibodies were well-tolerated. Like any medication, there were some side effects, or Adverse Events (AEs), as we call them in trials. The most common ones that showed up more in the combination groups than in the placebo group were muscle spasms and mouth ulcerations (like canker sores). These were mostly mild to moderate.

It’s worth noting that another antibody targeting ActA (garetosmab, one of the antibodies used here) has had some tolerability concerns in patients with a rare condition called fibrodysplasia ossificans progressiva (FOP). However, FOP is a very complex disease involving abnormal signaling, and the safety profile seen in those patients wasn’t observed in our study of otherwise healthy individuals. This suggests the AEs in FOP might be disease-specific. In our healthy volunteers, garetosmab alone and in combination with the GDF8 antibody was generally well-tolerated.

We didn’t see any major red flags in vital signs, blood tests, or other safety markers. And importantly, nobody developed antibodies against the study drugs themselves, which can sometimes be a problem with antibody therapies.

Unlocking Muscle Potential: The Future Looks Strong

This study is pretty exciting because it’s the first time we’ve shown in humans that GDF8 and ActA really are the *main* negative regulators of muscle mass. Blocking them together seems to be a powerful way to boost muscle growth and reduce fat.

Why is this a big deal? Well, think about people struggling with muscle loss – the elderly, those recovering from illness, or even people losing weight rapidly. Increasing muscle could make a huge difference in their strength, mobility, and metabolic health.

Speaking of weight loss, modern approaches like GLP-1 agonists (think Ozempic, Wegovy, etc.) are fantastic for shedding pounds, but they can also lead to significant muscle loss along with fat loss. That’s not ideal. Our preclinical work, and ongoing clinical trials, are exploring if combining these muscle-boosting antibodies with GLP-1 agonists could help people lose fat *without* losing valuable muscle. That could be a game-changer for treating obesity more effectively and healthily.

Now, let’s be real. This was a Phase 1 study. It was small, mainly in postmenopausal women (though we expect the findings are likely generalizable to men too, based on animal data), and designed primarily for safety. The DXA measurements, while useful, can be a bit variable, especially in smaller groups. So, we need bigger, longer studies to really confirm these effects and understand the full benefit-risk profile, especially in specific patient populations like those with muscle atrophy or obesity.

But these early results are incredibly promising. They suggest we might have found a way to override those ancient, energy-saving signals and help people build and keep the muscle they need for a healthier, stronger life in the modern world.

Source: Springer