Summary of Findings from a 2025 Nature Communications Study
GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) have revolutionized obesity treatment. However, these drugs don’t just burn fat — they also strip away muscle mass. In fact, up to 40% of weight lost on GLP-1s can come from lean tissue, especially muscle. This muscle loss can undermine metabolism and lead to rapid fat regain when treatment stops.
But what if we could change that?
A new study published in Nature Communications (2025) explored a powerful solution: dual blockade of myostatin (GDF8) and activin A, two proteins known to suppress muscle growth. The researchers found that this combination not only preserved muscle mass during GLP-1–induced weight loss — it actually enhanced fat loss and improved metabolic health in both obese mice and non-human primates.
Why Muscle Loss on GLP-1 Drugs Is a Problem
GLP-1 agonists work by suppressing appetite, leading to significant caloric restriction. But when calories drop, the body shifts into survival mode. It sheds muscle to reduce energy expenditure — a strategy that may have once helped our ancestors survive famine, but today, it backfires.
Muscle is metabolically active. Losing it makes it harder to maintain weight loss, worsens body composition, and increases the risk of issues like insulin resistance and fatty liver disease. Worse, most people regain the lost weight as fat, not muscle, after stopping treatment.
The Science: Blocking GDF8 and Activin A
The study used two fully human antibodies developed by Regeneron Pharmaceuticals:
- Trevogrumab (anti-myostatin)
- Garetosmab (anti-activin A)
When combined with semaglutide in obese animals, this treatment produced striking results.
In Obese Cynomolgus Monkeys:
- Fat mass dropped by ~40% in the combination group, compared to ~25% with semaglutide alone — a 15% increase in fat loss
- Lean mass increased by ~7% in the combination group, reversing GLP-1–induced muscle loss
- Antibody treatment alone (no GLP-1) led to a ~3% gain in lean mass
- These effects occurred without additional caloric restriction, suggesting that muscle preservation increased energy expenditure
This mirrors findings in obese mice and aligns with earlier human trials (in non-obese subjects), where GDF8/ActA blockade led to significant muscle gain and fat loss.
Transparency: This Study Was Run by the Drug Developer
It’s important to note that the study was conducted and funded by Regeneron Pharmaceuticals, which is actively developing these antibodies for clinical use. All listed authors were Regeneron employees or shareholders, and some hold a provisional patent related to this therapeutic approach.
While the data are compelling, this close connection to the drug’s commercial development warrants healthy skepticism. Results need to be replicated independently and in diverse human populations — especially since the animal studies included only males.
Benefits of Combining GLP-1 with GDF8 + ActA Blockade
| Benefit | GLP-1 Alone | GLP-1 + GDF8/ActA Blockade |
|---|---|---|
| Lean Mass | ↓ (loss) | ↑ ~7% gain |
| Fat Mass | ↓ ~25% | ↓ ~40% |
| Liver Health | Improved | Greatly Improved |
| Metabolic Markers | Improved | Most Improved |
| Long-Term Weight Quality | Compromised | Optimized |
Final Thoughts
Weight loss isn’t just about the number on the scale — it’s about what you lose. Muscle or fat? Function or fragility? This study suggests we may be on the verge of a new generation of obesity therapies that enhance fat loss while preserving the body’s most metabolically valuable tissue: muscle.
Still, more research is needed — particularly independent human trials. But if these results hold true in clinical settings, combining GLP-1 therapies with muscle-preserving antibodies could redefine the quality of weight loss.
Reference:
Mastaitis, J.W., Gomez, D., Raya, J.G., Li, D., Min, S., Stec, M., Kleiner, S., McWilliams, T., Altarejos, J.Y., Murphy, A.J., Yancopoulos, G.D., & Sleeman, M.W. (2025). GDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates. Nature Communications, 16, 4377.
