ACE-031 Peptide: Scientific Overview, Benefits, Side Effects, and More in Preclinical Studies

Muscle loss remains one of the toughest challenges to medicine. This is true whether it is due to aging, genetic conditions, or chronic illness.

Researchers have been investigating myostatin inhibition as a way to promote muscle growth and preserve strength. Among the most studied compounds is ACE-031. The latter is a recombinant protein and research peptide.

Within laboratory settings, ACE-031 was observed to produce myostatin-inhibiting qualities that could lead to enhanced muscle production. This article will give you a clear overview of ACE-031 and how it can help with your own study.

What is ACE-031?

ACE-031 (or ACE 031) is referred to as ramatercept. It is a recombinant fusion protein, aside from being classified as a research peptide. This means that ACE-031 is created by combining a specific section of activin receptor type IIB (ActRIIB) with the Fc portion of human IgG1.

Acceleron Pharma and Shire Pharmaceuticals developed this protein material. The goal is to potentially block molecules that inhibit muscle growth. Examples of such molecules are myostatin and activin A. Current research suggests that through this action, ACE-031 could have potential effects on muscle mass and strength.

How ACE-031 Works: Mechanism of Action

To better understand how ACE-031 produces its effects, it is vital that we discuss first what normal physiology looks like, how the compound influences it, and the expected outcome of such an action.

Normal physiology

Myostatin is a known natural regulator of muscle development. Under normal conditions, it binds to the activin type IIB receptor (ActRIIB). This interaction will trigger a cascade of intracellular signals that will limit muscle growth, proliferation, and differentiation. With this quality, myostatin acts as a brake to prevent uncontrolled hypertrophy.

ACE-031’s role

ACE-031 is characterized as a soluble fusion protein. It was engineered to specifically link the extracellular domain of ActRIIB with the Fc portion of human IgG1. In research settings, this molecule circulates freely and binds to myostatin and other ligands.

When it occupies the mentioned ligands, ACE-031 may act as a decoy receptor. This action prevents the ligands from sending their usual “stop” signal through ActRIIB in muscle tissue, which would otherwise limit muscle growth.

Expected Outcome

When ACE-031 captures myostatin and related ligands in experimental models, the usual “brake” on growth will be released. The downstream effects in preclinical studies include: 

• Increased muscle mass: Muscle fibers grow larger across different types. This is because the signals that normally restrict growth are reduced.
• Improved muscle strength and contractility: Animals in experimental studies showed greater ability to generate force and improved muscle performance.
• Bone and metabolic changes: Research findings also point to a potential increase in bone mineral density and better insulin sensitivity. This effect provides information on the broader influence of the ActRIIB pathway in the body.

Preclinical Benefits of ACE-031 (Animal & Lab Studies)

Because ACE 031 may inhibit myostatin and related ligands, it has been investigated to understand pathways associated with muscle growth, energy metabolism, and bone health.

Potential Promotion of Muscle Tissue Development

Several research studies report that ACE 031 has the potential to stimulate muscle hypertrophy. As such, this is one of the consistent findings across preclinical research for ACE 031. As the compound prevents myostatin from binding to its natural receptor, muscle cells may proliferate and enlarge. [1]

• In mouse models, researchers documented up to a 40% increase in muscle volume. This was observed in specific muscle groups following administration.
• Such findings highlight ACE 031 as a robust model compound for studying muscle growth pathways.

Potential Enhancement of Bone Strength

ACE-031 research has also led to results that go beyond muscle tissue. Some studies indicate that by blocking ActRIIB signaling, the experimental chemical may influence bone remodeling and density. [2]

• Research models showing postmenopausal symptoms were observed to demonstrate an increase in lumbar spine bone mineral density.
• In other experimental setups, exposure to ACE 031 resulted in improved bone mineral density and biomechanics. This finding suggests a potential link between myostatin and skeletal strength.

Potential Improvement for Muscle Atrophy Disorders

ACE-031 was originally studied as a possible therapy for Duchenne Muscular Dystrophy (DMD), cancer-related cachexia, and age-related sarcopenia. [3]

• In a clinical study involving models with DMD, an increase in lean body mass was attributed to ACE-031. Furthermore, the compound is also believed to produce improved mobility in test performance.
• Other studies continue to utilize ACE 031 as a reference tool for investigating muscle degeneration and repair mechanisms.

Potential Augmentation for Energy Metabolism

Myostatin has been implicated in muscle fatigue and energy dysregulation. Now, certain research into ACE-031 points to specific metabolic effects: [4]

• In mdx mouse studies, myostatin inhibition altered oxidative capacity. Thus, it might lead to improved muscle energy utilization and contractile force generation.
• Interestingly, results included enhanced force production of up to 40%. When this occurs, the researchers even observed that there were no significant changes in ATP homeostasis.
• However, some data provided caution about ACE-031 in this area. ActRIIB blockade could reduce muscle capillarization. 

Potential Muscle Preservation in Cancer Research

Muscle wasting (cachexia) is a significant complication of many cancers. Some preclinical findings suggest ACE-031 may help play a role in this setting.

• In cell culture studies, ACE-031 appeared to reduce muscle fiber atrophy. It even helped preserve mitochondrial function and improve energy efficiency under metabolic stress. [5]
• Some researchers have proposed that by blocking myostatin, the experimental compound may indirectly reduce inflammation. It could also support both muscle and bone metabolism in models of cancer-induced cachexia.

Despite this promising effect, ACE-031 is not an approved treatment for cancer or its symptoms. More clinical studies are required to explore its possible positive effects on the disease. 

Other Potential Applications

Beyond direct muscle growth, ACE-031 can also offer a valuable framework for studying the interconnected biology of muscle, fat, and bone tissues. Some reported outcomes from early tests suggest potential links to:

• Reduced fat accumulation [6]
• Improved bone density [7]
• Enhanced insulin sensitivity [8]

These multifaceted effects only underscore ACE-031’s relevance as a research tool, not a therapeutic agent.

IMPORTANT: The stated potential benefits of ACE-031 are limited only to laboratory settings. This product is sold for research purposes only. It is not approved for human consumption. The findings mentioned in this post should be interpreted as part of ongoing research that needs further exploration, rather than therapeutic advice.

Possible Side Effects Observed in Preclinical Studies

While ACE-031 has provided valuable insights into muscle and skeletal biology, studies have also reported unwanted effects.

In some research settings, ACE-031 was observed to influence blood vessel biology. Some reported outcomes include nose bleeding, gum bleeding, and the appearance of small surface blood vessels (telangiectasia).

Legal Status & Research Context

• Not FDA-approved: ACE-031 is not approved for human use and remains a research compound.
• Research only: The product is available strictly for laboratory and preclinical research. Any outside use is not recommended and may be unsafe.

Comparison with Other Myostatin Inhibitors

ACE 031 is part of a broader class of myostatin inhibitors. Each with slightly different mechanisms:

• Stamulumab (MYO-029): This compound is a monoclonal antibody against myostatin. It was able to show modest muscle gains but failed in late-stage trials.
• Bimagrumab: This product is an antibody that blocks ActRIIB directly. It was alleged to demonstrate muscle increase but produced mixed results in functional outcomes.
• Follistatin–based therapies: This is another approach that involves natural myostatin-binding proteins.

Key difference: ACE-031 was unique because it blocked multiple ligands (myostatin, activins, GDFs), potentially explaining its stronger effects—but also its higher risk profile.

Conclusion

ACE-031 represented one of the most promising attempts at unlocking the power of myostatin inhibition. Preclinical studies demonstrated noticeable improvements in muscle, bone, and metabolic health within experimental settings. However, clinical development of the compound was stopped due to some safety concerns.

While waiting for further preclinical studies, ACE-031’s research helped us understand another targeted approach to address muscle loss.

References

1. Béchir, N., Pecchi, E., Vilmen, C., Le Fur, Y., Amthor, H., Bernard, M., Bendahan, D., & Giannesini, B. (2016). ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo. The FASEB Journal, 30(10), 3551–3562. https://doi.org/10.1096/fj.201600271rr
2. Attie, K. M., Niels Geert Borgstein, Yang, Y., Condon, C. H., Wilson, D. K., Pearsall, A. E., Kumar, R., Willins, D. A., Jas Seehra, & Sherman, M. L. (2013). A single ascending-dose study of muscle regulator ace-031 in healthy volunteers. Muscle & Nerve, 47(3), 416–423. https://doi.org/10.1002/mus.23539
3. Puolakkainen, T., Ma, H., Kainulainen, H., Pasternack, A., Rantalainen, T., Ritvos, O., Heikinheimo, K., Hulmi, J. J., & Kiviranta, R. (2017). Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy. BMC Musculoskeletal Disorders, 18(1). https://doi.org/10.1186/s12891-016-1366-3 
4. Attie, K. M., Niels Geert Borgstein, Yang, Y., Condon, C. H., Wilson, D. K., Pearsall, A. E., Kumar, R., Willins, D. A., Jas Seehra, & Sherman, M. L. (2013). A single ascending-dose study of muscle regulator ace-031 in healthy volunteers. Muscle & Nerve, 47(3), 416–423. https://doi.org/10.1002/mus.23539 
5. Blockade of ActRIIB Signaling Triggers Muscle Fatigability and Metabolic Myopathy. (2014). Molecular Therapy, 22(8), 1423–1433. https://doi.org/10.1038/mt.2014.90 
6. Attie, K. M., Niels Geert Borgstein, Yang, Y., Condon, C. H., Wilson, D. K., Pearsall, A. E., Kumar, R., Willins, D. A., Jas Seehra, & Sherman, M. L. (2013). A single ascending-dose study of muscle regulator ace-031 in healthy volunteers. Muscle & Nerve, 47(3), 416–423. https://doi.org/10.1002/mus.23539 
7. McPherron, A. C., Lawler, A. M., & Lee, S. J. (1997). Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature, 387(6628), 83–90. https://doi.org/10.1038/387083a0 
8. Shiuchi, T., Cui, T.-X., Wu, L., Nakagami, H., Takeda-Matsubara, Y., Iwai, M., & Horiuchi, M. (2002). ACE Inhibitor Improves Insulin Resistance in Diabetic Mice via Bradykinin and NO. Hypertension, 40(3), 329–334. https://doi.org/10.1161/01.hyp.0000028979.98877.0c