PerformanceRAP-031ActRIIB-Fc

ACE-031

Myostatin/activin 'ligand trap' fusion protein · discontinued over a bleeding signal · WADA-banned

ACE-031 is a discontinued experimental drug whose story is a clean lesson in why 'more muscle' is not the same as 'safe.' It is not a small peptide but a fusion protein — the catching part of the activin receptor type IIB (ActRIIB) stitched onto an antibody fragment — engineered to act as a 'ligand trap.' Floating in the blood, it soaks up myostatin (the body's main brake on muscle growth) along with related signaling molecules like activin A and GDF-11, before they can reach their receptors. Take the brake off, and muscle grows. In a single-dose study in healthy postmenopausal women, one dose increased total lean body mass by about 3.3% and thigh-muscle volume by about 5%, while lowering fat — a real anabolic signal. But the molecule was dropped, and the reason is the important part. In a Phase 2 trial in boys with Duchenne muscular dystrophy, dosing was stopped after the second regimen because of bleeding-related side effects: nosebleeds (epistaxis) and telangiectasias (small dilated blood vessels visible in the skin). These came from the trap's lack of selectivity — it also blocks signaling molecules (the BMP/activin family) that the body's blood vessels depend on. Acceleron ended the program around 2013 and moved on to more selective successor molecules. ACE-031 was never approved for anything, and myostatin inhibitors like it are explicitly banned in sport by WADA. Net: it worked on muscle, but its off-target effect on blood vessels is why it has no future as a drug.

The short version

ACE-031 is best understood as a sponge for the signals that hold muscle growth back. Your body makes a protein called myostatin whose job is to limit how big muscles get — a built-in brake. ACE-031 is a lab-made decoy: it carries the same 'catcher' part that myostatin would normally dock onto, but floating loose in the bloodstream. So myostatin (and a few related signals) get mopped up before they reach real receptors, the brake comes off, and muscle grows.

It did work on muscle. In a careful single-dose study in healthy older women, one injection raised lean body mass by about 3.3% and thigh-muscle volume by about 5%, and lowered body fat. That is a genuine, measurable anabolic effect — the kind of result that makes a drug interesting.

So why is it discontinued? Because the same sponge also soaks up signals the body's blood vessels need. In a trial in boys with Duchenne muscular dystrophy, doctors had to stop dosing because of bleeding problems — nosebleeds and little dilated blood vessels appearing in the skin (telangiectasias). That off-target effect on blood vessels was the dealbreaker. The company shut the program down around 2013 and shifted to newer, more selective molecules. ACE-031 was never approved for any use, and drugs that block myostatin this way are banned in sport. The honest summary: real muscle effect, unacceptable blood-vessel side effect.

Molecular identity

Specs

Type: Soluble fusion PROTEIN (biologic) — ActRIIB extracellular domain fused to human IgG1 Fc; a ligand trap / decoy receptor. NOT a small molecule or short peptideUniProt Q13705; PMID 23169607
Receptor of origin: Activin receptor type IIB (ActRIIB), gene ACVR2BUniProt Q13705
Ligands trapped: Myostatin (GDF-8), activin A, GDF-11 and related TGF-β-superfamily ligandsPMID 23169607
Molecular formula / single PubChem CID: Not applicable — Fc-fusion protein, not a defined small moleculeBy definition (biologic)
Half-life: Mean terminal t½ ≈ 10–15 days (single SC dose, healthy postmenopausal women)PMID 23169607Half-life curve →
Development status: DISCONTINUED — DMD Phase 2 halted (announced April 2011) for a bleeding signal; program ended ~2013; never approvedPMID 27462804; sponsor disclosures
WADA status: PROHIBITED at all times — S4.3 (agents preventing activin receptor IIB activation); ACE-031 named as an exampleWADA Prohibited List S4.3

Plain English

Mechanism

ACE-031 is a 'ligand trap.' Muscle growth is restrained by myostatin (also called GDF-8), which signals through a cell-surface receptor called the activin receptor type IIB (ActRIIB). ACE-031 is built by taking the ligand-catching outer portion of that receptor and fusing it to the Fc region of an antibody (which makes it stable and long-lived in the blood). The result is a soluble decoy that circulates and binds myostatin before it can dock onto the real receptors on muscle — so the growth-restraining signal never gets delivered, and muscle is de-repressed.

Crucially, ActRIIB is not myostatin-specific. The same receptor — and therefore the same trap — also binds activin A, GDF-11, and several bone-morphogenetic proteins (BMPs). This broad reach is what makes the trap powerful, because it removes several muscle-restraining brakes at once.

But that lack of selectivity is also the mechanism's fatal flaw. The activin/BMP signaling that ACE-031 mops up is not just about muscle — it is essential to the integrity and behavior of blood vessels. Trapping those vascular ligands is the mechanistic explanation for the bleeding side effects (nosebleeds and dilated surface vessels) that stopped the drug's development. In other words, the very breadth that makes the trap effective on muscle is what makes it dangerous to the vasculature.

Sources:PMID 23169607 PMID 27462804

Why people reach for it

Potential benefits

ACE-031's appeal has to be read against its history: it produced a real muscle effect in one study, but it was discontinued over a bleeding safety signal and never approved. What people are drawn to — and why it's a cautionary tale, not a recommendation.

A measured muscle gain in one study — Its genuine draw. In a single-dose study in healthy postmenopausal women, one injection raised total lean body mass by about 3.3% and thigh-muscle volume by about 5.1% while lowering fat — a real, measured anabolic signal, though from a single dose only.
Removes the myostatin brake — As a soluble activin-receptor IIB trap it mops up myostatin (the body's main brake on muscle growth) along with activin A and GDF-11 before they reach their receptors — the mechanism behind the lean-mass result.
A bone-formation signal too — The same single-dose study reported raised bone-formation markers alongside the muscle effect — a secondary finding from the activin-pathway blockade.
Long-acting by design — Engineered with an antibody-fragment (Fc) fusion, its terminal half-life ran roughly 10–15 days in the single-dose study, which was meant to allow infrequent dosing.
Honest caveat: discontinued over bleeding — The defining fact. Repeat dosing in a Duchenne trial caused nosebleeds (epistaxis) and dilated surface vessels (telangiectasias) from off-target trapping of vascular signals, the program was halted, it was never approved, and it's WADA-banned — so the muscle effect is real but the molecule has no future as a drug.

Sources:PMID 23169607 PMID 27462804

What people are drawn to ACE-031 for, drawn from its limited trial record (one single-dose study, then a halted repeat-dose trial) — not proven, ongoing, or approved outcomes, and not a medical claim.

Implied timing

Best time to dose

Implied best time

Anytime (consistent)

Time of day is irrelevant for ACE-031 — it's a long-acting ligand trap, so what matters is dosing consistency across its (short, discontinued-drug) use, not the hour.

ACE-031 works by trapping myostatin and related ligands as a long-lived decoy receptor, not by pulsing with any hormonal rhythm — and with a terminal half-life of roughly 10–15 days (single-dose data), a single injection acts across weeks, so the clock time of that injection has no bearing on the effect.
Because the action is slow and systemic, consistency in the dosing interval — in the trials it was given every 2–4 weeks — matters far more than what time of day a dose lands.
As a subcutaneous protein it doesn't interact with food timing, so meals don't pin the dose to any part of the day.
Honest limit: there is no validated or approved dose at all — ACE-031 was discontinued after a repeat-dose bleeding signal — so any timing here is convention for a graveyard-tier compound, and that same long half-life means it can't be cleared quickly if an adverse effect appears.

No study establishes an ideal time of day for ACE-031 — this is reasoned from its long half-life and trap mechanism. Most peptide dosing lands in the midday-to-evening window; for ACE-031 time of day is irrelevant, and consistency across its (discontinued) use is the only thing that would matter.

Sources:PMID 23169607

How to run it

Dosing & protocol

ACE-031 was given by subcutaneous injection in both human studies — there is no oral form for a protein this size. The sections below cover the trial dose as a factual reference, the administration route as it was used, the reason the program was halted, and the reconstitution math the calculator runs from. There is no approved or validated dose: ACE-031 was discontinued before any clinical dose was established as safe for repeat use.

Trial figures for reference only — not a dosing recommendation. ACE-031 was discontinued after a vascular bleeding signal emerged with repeat dosing; no dose has been validated as safe, and no legitimate commercial supply exists. WADA S4.3 prohibits it at all times.

Trial dose (for reference only)

The single-dose healthy-volunteer study is the only completed trial with a clean safety read. Its numbers are given here as the factual record — not a protocol to follow.

Studied range:: 0.02 to 3 mg/kg as a single subcutaneous dose in 48 healthy postmenopausal women (Attie 2013). The muscle effect at the top dose: +3.3% total lean body mass, +5.1% thigh-muscle volume, reduced fat, raised bone-formation markers — measurable and real.
Why this is the ceiling of the reference:: The single dose was generally well tolerated. The repeat-dose DMD trial — every 2–4 weeks — was stopped after the second regimen for bleeding (epistaxis and telangiectasias). Any use producing a sustained effect requires repeat dosing, and repeat dosing is where the program was halted. The single-dose tolerability cannot be read as overall safety.
No approved dose exists:: Development ended around 2013; no regulatory body has established a safe or recommended dose for ACE-031 for any indication. Vendor-circulated mg/kg values are extrapolations from trial ranges, not endorsed figures.

Subcutaneous administration

Both trials used subcutaneous injection — the only viable route for a large protein that would be digested if swallowed.

Injection site:: Abdomen (keeping a few inches clear of the navel), the outer thigh, or the love-handle area. Rotate sites between administrations to prevent local irritation at a single spot.
Frequency in trials:: Phase 1 healthy-volunteer: single dose. Phase 2 DMD (halted): every 2–4 weeks. The long half-life (~10–15 days from the Attie 2013 data) was designed to support infrequent dosing — but it also means the drug cannot be cleared quickly if an adverse effect appears.
Food and timing:: As a subcutaneous protein, ACE-031 does not interact with food timing — this is not relevant in the way it is for small peptides competing for gut absorption. Time of day is irrelevant given the ~10–15 day half-life; consistency in the dosing interval is all that matters — see Best time to dose above.

Why it was discontinued

The vascular bleeding signal is not a theoretical risk — it is the documented reason the program was halted, and it traces directly to the mechanism.

What happened:: In the Phase 2 DMD trial (n=24, repeat dosing every 2–4 weeks), the study was stopped after the second dosing regimen due to epistaxis (nosebleeds) and telangiectasias (small dilated blood vessels visible at the skin surface). These were spontaneous vascular events, not injection-site reactions.
Why it happened (mechanism):: ActRIIB is not selective for myostatin. The same trap that mops up myostatin also blocks activin A, GDF-11, and BMP-family ligands that blood vessels depend on for their integrity and signaling. The broader the trap, the more vascular off-target effect. Narrowing selectivity is the engineering challenge Acceleron's successor molecules were designed to solve.
Program halt timeline:: Dosing stopped April 2011. The Acceleron/Shire collaboration formally ended around May 2013. No further ACE-031 development was pursued under this molecule.
What this means for use:: The bleeding signal is a repeat-dose phenomenon — which is exactly the dosing context any real use requires. There is no dose, schedule, or cofactor protocol that has been shown to mitigate the off-target vascular effect; it is intrinsic to the mechanism of this molecule as engineered.

Reconstitution at a glance

The on-page calculator runs this live. The placeholder defaults (10 mg vial, 2 mL BAC water) give a nominal concentration only — no validated dose exists to anchor a real target.

Mixing (placeholder):: 10 mg vial + 2 mL bacteriostatic water = 5,000 mcg per mL. On a 100-unit (1 mL) insulin syringe: 1,000 mcg = 20 IU. Adjust the calculator inputs to any target — the math is the same regardless of vial size.
Protein handling:: ACE-031 is a large Fc-fusion protein, more fragile than short synthetic peptides — the biologic convention is to never shake the vial (shaking denatures Fc-fusion proteins); roll or swirl gently to mix.

Sources:PMID 23169607 PMID 27462804

Substrate the signal needs

Nutritional cofactor precision

Three questions drive cofactor reasoning for any myostatin-trapping agent: what substrate does brake-removal consume (SUPPLY), what does it amplify (AMPLIFY), and what does it mitigate (MITIGATE)? For ACE-031 the MITIGATE question dominates — because the vascular bleeding signal that killed this program is mechanistic, not nutritional, and no cofactor offsets it.

Reasoned from the muscle-building substrate logic shared by all myostatin inhibitors plus the vascular-bleeding mechanism specific to ACE-031 — not from an ACE-031 cofactor study (none exists). The honest headline: there is no nutrient protocol that makes a discontinued bleeding-risk biologic safe to use.

What no cofactor can fix (the vascular signal)

The most important thing to understand about ACE-031's cofactor picture is what is missing from it.

The mechanism is structural, not nutritional:: ACE-031 bleeds blood vessels because it traps BMP/activin ligands those vessels depend on — a consequence of the trap's breadth, not a deficiency the body can compensate for with zinc, vitamin C, or fish oil. Narrowing the trap's selectivity is an engineering problem, not a dietary one; it is why Acceleron's successor molecules are different molecules.
Bleeding-risk compounders to avoid:: If anyone were to use this molecule, the rational 'anti-cofactor' list is things that raise bleeding risk: anticoagulants (warfarin, apixaban), antiplatelet drugs (aspirin at therapeutic dose, clopidogrel), and high-dose omega-3 fatty acids (≥3–4 g EPA/DHA/day) all compound the vascular fragility this molecule already causes. These are not cofactors to add — they are contraindications to the drug's own problem.
Honest summary:: The safest cofactor protocol for a discontinued bleeding-risk biologic is not to use it. This section exists because the substrate and amplifier questions have real answers — but the mitigate answer is that no nutrient protocol answers the vascular question, and that is the one that matters.

Muscle-building substrate (SUPPLY — if the brake were removed)

Removing the myostatin brake does not itself build muscle — it only removes a ceiling. The actual construction still requires the same inputs every hypertrophy effort needs.

Protein + leucine:: ~1.6–2.2 g protein per kg of bodyweight per day, with leucine content sufficient to trigger the mTOR anabolic signal (~2.5–3 g leucine per meal, hit easily from whole protein sources). The brake-removal raises the ceiling; protein builds what goes up to it.
Calorie surplus:: A modest surplus (~200–400 kcal/day above maintenance) provides the energy budget for new tissue synthesis. Brake-removal without surplus yields redistribution, not net gain.
Resistance training:: The mechanical stimulus directs where new muscle is added. Without progressive resistance training, the anabolic environment is undirected — true for GH, IGF-1, and myostatin inhibitors equally.
Creatine monohydrate:: 3–5 g daily. The one well-supported sports-nutrition adjunct to training output, via phosphocreatine replenishment. Nothing ACE-031-specific — general lean-mass hygiene.

Combinations + timing

Stacking notes + timing windows

ACE-031 has no responsible recommended stack. Its defining feature — broad ActRIIB ligand trapping — is also the mechanism behind the bleeding signal that ended its program. The honest answer to 'what stacks well with ACE-031?' is a caution map, not a protocol.

Combinations reasoned from mechanism — not studied head-to-head, and ACE-031 itself has no approved use. WADA S4.3 prohibits ACE-031 and the entire myostatin-inhibitor class at all times. Treat this section as a safety-forward thought experiment.

ACE-031 + Follistatin-344 — do not combine

Follistatin is the combination this molecule's history most specifically warns against.

Why this is not a stack — it doubles the same lever:: Follistatin-344 inhibits the same myostatin/activin pathway from a different angle — it binds activin, myostatin, and GDF-11 directly. Combining it with ACE-031 does not add a complementary mechanism; it concentrates the same activin/BMP-trapping effect. Two traps on the same signaling pool is redundant on muscle, but additive on vascular off-target effect.
The compounded risk:: The bleeding signal in ACE-031's DMD trial came from off-target BMP/activin trapping on blood vessels. Follistatin traps overlapping ligands. Stacking them concentrates the same vascular off-target effect that already halted ACE-031's program — compounding an already-discontinued safety profile.
The rule:: Never stack two agents that inhibit the same myostatin/activin pathway. The redundancy buys no additional muscle benefit while the vascular risk is additive. This combination should be treated as contraindicated given ACE-031's history.

ACE-031 + GH secretagogue (e.g., Ipamorelin, CJC-1295) — theoretical only, with compounding unknowns

The GH/IGF-1 axis is a complementary lever — it builds tissue through a different pathway than myostatin trapping — but this is reasoning in a vacuum.

Why the mechanism is complementary in theory:: GH secretagogues like Ipamorelin + CJC-1295 drive anabolism via the GH → IGF-1 axis, which is a parallel pathway to myostatin inhibition, not an overlapping one. In principle, removing the myostatin ceiling while driving IGF-1-mediated protein synthesis addresses two different brakes.
Why this remains theoretical:: ACE-031 has no legitimate supply, no approved dose, and a repeat-dose vascular bleeding signal. A theoretical GH/IGF-1 stack does not resolve any of those problems. The interaction between ActRIIB-Fc ligand trapping and exogenous GH pulse amplification has never been characterized in any human or animal study.
The honest framing:: This entry exists to explain the mechanism logic that circulates in research communities — not to endorse the combination. Any ACE-031 stack is a safety-forward thought experiment, not a protocol.

Reconstitution math

Reconstitution calculator

Calculated for a 1 mL U-100 insulin syringe (100 units/mL).

Peptide per vial

BAC water added

Desired dose

Units per dose

Draw to this mark on a U-100 syringe

Volume per dose: 0.2 mL
Doses per vial: 10
Concentration: 5 mg/mL

One vial lasts

Daily: 10 days
Every other day: 20 days
5×/week: 14 days

Research use only. Not for human consumption. Outputs are reference values based on research literature — verify all measurements independently.

From the studies

Side effects from research

The defining safety problem is vascular bleeding. In the Duchenne muscular dystrophy trial, repeat dosing produced epistaxis (nosebleeds) and telangiectasias (small dilated blood vessels visible at the skin surface), and these spontaneous bleeding/vascular events were serious enough to stop the trial after the second dosing regimen. They are attributed to the trap's off-target inhibition of BMP and activin signaling that blood vessels depend on — a direct consequence of the mechanism, not an incidental finding.

In the single-dose healthy-volunteer study the drug was 'generally well tolerated,' with injection-site redness the most common complaint — but that reassurance applies only to one dose. The bleeding signal is a repeat-dose phenomenon, which is exactly the dosing pattern any real use would require, so the single-dose tolerability should not be read as overall safety.

Because development was halted, there is no long-term human safety database. Two further facts frame the risk: ACE-031 was never approved for any condition, and myostatin inhibitors of this class are prohibited in sport by the World Anti-Doping Agency at all times — using one is a doping violation as well as an uncharacterized medical risk.

Sources:PMID 27462804 WADA S4.3

As reported in literature

Research dosing ranges

The table below contrasts the two trials that tell ACE-031's whole story: a single-dose study showing a real muscle effect, and a repeat-dose pediatric trial halted for bleeding. Doses are framed as research-studied amounts, not recommendations; route was subcutaneous. No approved dose exists.

Dose	Route	Model	Outcome	Sources:
0.02–3 mg/kg, single dose	Subcutaneous	Human — healthy postmenopausal women (Attie 2013, n=48)	At 3 mg/kg: +3.3% total lean body mass, +5.1% thigh-muscle volume, reduced fat, raised bone-formation markers; generally well tolerated as a single dose	PMID 23169607
Repeat dose, every 2–4 weeks	Subcutaneous	Human — boys with Duchenne muscular dystrophy (Campbell 2017, n=24)	STOPPED after the second regimen for bleeding (epistaxis, telangiectasias); only non-significant efficacy trends — the safety signal that ended development	PMID 27462804

Quick answers

Frequently asked

Is ACE-031 a peptide?

Not in the usual sense — it is a fusion protein (a biologic), not a short synthetic peptide. It is the ligand-catching part of the activin receptor type IIB joined to an antibody fragment (IgG1 Fc), engineered to circulate in the blood and trap myostatin and related signals. It has no single small-molecule formula.

Does ACE-031 build muscle?

Yes, in the limited testing done. In a single-dose study in healthy postmenopausal women, lean body mass rose about 3.3% and thigh-muscle volume about 5% within roughly a month, with reduced fat. That anabolic effect is real — but it was never developed into an approved treatment because of safety problems with repeat dosing.

Why was ACE-031 discontinued?

Because of bleeding. In a Phase 2 trial in boys with Duchenne muscular dystrophy, repeat dosing caused nosebleeds (epistaxis) and dilated surface blood vessels (telangiectasias), so dosing was stopped after the second regimen. The cause is the drug's lack of selectivity — it also blocks BMP/activin signals that blood vessels rely on. The program ended around 2013.

How does the 'ligand trap' work?

Myostatin and related molecules normally limit muscle growth by signaling through the activin receptor type IIB. ACE-031 is a soluble copy of that receptor's catching region, floating free in the blood. It binds those signals before they reach the real receptors, so the growth-limiting message never gets delivered and muscle grows.

Is ACE-031 banned in sport?

Yes. The World Anti-Doping Agency prohibits agents that prevent activin receptor IIB activation (myostatin inhibitors) at all times, and ACE-031 is named as an example of a decoy activin receptor. Using it is a doping violation, in addition to the fact that it is a discontinued drug with an unresolved safety problem.

Primary sources

References

PMID 23169607Attie et al., Muscle & Nerve 2013 — single ascending-dose Phase 1 in 48 healthy postmenopausal women; +3.3% lean mass at 3 mg/kg; half-life ~10–15 days
PMID 27462804Campbell et al., Muscle & Nerve 2017 — ACE-031 in ambulatory boys with Duchenne muscular dystrophy (n=24); halted for epistaxis and telangiectasias
UniProt Q13705UniProt Q13705 (ACVR2B_HUMAN) — activin receptor type-2B, the receptor whose extracellular domain forms ACE-031's trap
WADA S4.3WADA Prohibited List, S4.3 'Agents Preventing Activin Receptor IIB Activation' — ACE-031 named; prohibited at all times

Research use only · Not medical advice · Updated 2026-06-01