ACE-031 is not a peptide in the usual sense - it's a bigger, engineered protein made by fusing part of a muscle receptor to an antibody fragment. It was built to block myostatin and a few related molecules that normally tell muscle to stop growing. Researchers tested it in two small human trials, one in healthy older women and one in boys with Duchenne muscular dystrophy, plus a long list of animal studies. The human program was stopped in 2011 after a small number of patients had nosebleeds and skin blood-vessel changes, and it was never brought back or approved. It shows up today mostly as a black-market research chemical and on doping-control watch lists, not as a medicine you can legally obtain.
How strong is the evidence?
There are two real human trials: a single-dose safety study in 48 healthy postmenopausal women, and a small placebo-controlled trial in boys with Duchenne muscular dystrophy. Both showed muscle-mass signals, but the DMD trial was stopped early for safety reasons before it could prove a real functional benefit. Everything else - and there is a lot of it - is mouse, rat, or monkey research on the same biology (myostatin blocking), which consistently grows muscle in animals but doesn't tell you what happens in a person over months or years. No regulator has approved ACE-031 for any use.
Uses
What people use it for
Muscle-wasting disease research (Duchenne muscular dystrophy)
Some human dataThe main reason ACE-031 was developed and tested in people was to try to slow muscle loss in boys with Duchenne muscular dystrophy, a genetic disease that destroys muscle over time.
General muscle-building research
Animal / labOutside of disease research, scientists have used ACE-031 as a tool to study how blocking myostatin affects muscle, bone, and fat in animals - not as something meant for healthy people to take.
Black-market bodybuilding use
AnecdotalDespite never being approved, ACE-031 is sold informally as a research chemical and is used off-label by some people chasing muscle growth. This is unsupervised, untested in this context, and the product itself is often not what it claims to be.
Potential benefits
What it may help with
Increases lean muscle mass
Some human dataIn the one human dose-finding trial, healthy older women given the highest dose gained about 3.3% more total lean body mass and 5.1% more thigh muscle volume after four weeks compared with placebo. Animal studies in mice, rats, and monkeys consistently show the same muscle-building effect.
May help preserve muscle and mobility in Duchenne muscular dystrophy
Some human dataIn the DMD trial, boys given ACE-031 showed a trend toward keeping their walking distance steady while boys on placebo declined, along with more lean mass and bone density. None of this reached statistical significance, and the trial was stopped early, so this is a hint, not proof.
Studies:27462804Builds muscle in confirmed non-human primates, not just rodents
Animal / labA study in marmoset monkeys found more lean body mass, bigger muscle fibers, and stronger muscle contractions after 14 weeks of treatment, which matters because primate results usually predict human effects better than mouse studies do.
Studies:41686840Increases bone density alongside muscle
Animal / labAcross many animal studies, blocking this pathway also increased bone volume and strength, helped fracture healing, and protected against bone loss from aging, low estrogen, or illness. The human DMD trial hinted at the same bone benefit, but only as a secondary, non-significant trend.
May counter muscle wasting from illness (cachexia)
Animal / labAnimal studies show this same class of protein can reverse muscle loss from cancer, HIV infection, and hormone-therapy for prostate cancer. This is a promising research direction but has not been confirmed for ACE-031 specifically in sick humans.
May reduce fat gain alongside building muscle
Animal / labMouse studies found this pathway-blocking approach can reduce fat gain and even trigger fat tissue to burn more energy. The DMD human trial also showed a trend toward less fat mass, but it was not the main finding and wasn't statistically confirmed.
What to watch for
Side effects & risks
- Moderate
Nosebleeds (epistaxis)
In the Duchenne muscular dystrophy trial, this side effect appeared often enough, along with visible small blood vessels under the skin, that the study sponsor stopped the trial's higher dosing plan.
- Moderate
Small visible blood vessels under the skin (telangiectasias)
Seen alongside the nosebleeds in the DMD trial. Together these two findings were the reason development of ACE-031 was halted.
- Mild
Injection-site redness
The most common side effect in the healthy-volunteer dosing study was mild redness where the shot was given.
- Serious
Possible thickening of the heart muscle wall
In monkeys given a related ActRIIB-blocking protein for 12 weeks, the heart's main pumping wall thickened more than in untreated animals, though overall heart function wasn't clearly worse. This kind of drug hasn't been tested in humans long enough to know if this is a real concern for people.
- Moderate
Muscle fatigue and metabolic strain with long-term blocking
In mice, blocking this pathway for four months caused the muscle to fatigue much faster and struggle to produce energy properly, even though the muscle itself was bigger. This suggests bigger muscle isn't automatically healthier muscle if this pathway is blocked for a long time.
- Serious
Black-market products may not contain real ACE-031
A lab analysis of 14 products sold online as ACE-031 found that only 12 contained any related protein at all, and none of them were the real drug - they were actually the full-length human activin receptor IIB, missing the antibody piece that makes real ACE-031 last in the body. Anyone buying this off the internet has no way of knowing what they are actually injecting.
Dosing
Dosing — what studies used
There is no approved or medically recommended dose because ACE-031 was never approved for any use and its development was stopped. What follows is strictly what researchers used in the two human trials that exist, reported here so you understand the studies - not as guidance for taking it yourself.
Healthy postmenopausal women, single-dose safety study
Human trial0.02 to 3 mg/kg (single dose, dose-escalation design)
One dose only · Measured out to 29 days · Subcutaneous injection
The 3 mg/kg dose produced the measurable increases in lean mass and thigh muscle volume. Half-life was 10-15 days, meaning the drug stays in the body for weeks after one shot.
Boys with Duchenne muscular dystrophy, placebo-controlled trial
Human trialAscending doses (exact amounts were not reported in the published results)
Every 2 to 4 weeks · Trial stopped early after the second dosing level, before completion · Subcutaneous injection
Stopped for safety concerns (nosebleeds and skin blood vessel changes), not because it didn't work - but this means long-term dosing in this population was never actually established.
Typical animal research dose (mice, rats, monkeys)
Animal study5 to 10 mg/kg
Once weekly, in most studies · 3 days up to 16 weeks depending on the study · Intraperitoneal, intramuscular, or intravenous depending on the study
Shown here only to illustrate how the drug class is generally dosed in research animals - these doses do not translate directly to a safe or effective human dose.
Because this drug lingers in the body for weeks after a single shot, any side effect can't be quickly reversed by stopping treatment. This is a medically supervised research drug, not something to self-dose, and any product bought outside a clinical trial has an unknown, unverified identity and purity.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Your muscles are constantly getting a 'stop growing' signal from a natural protein called myostatin, plus a few related molecules. That signal works by docking onto a receptor on muscle cells called ActRIIB. ACE-031 is built from a copy of that same receptor's docking site, glued onto part of an antibody so it lasts longer in the blood. Once injected, it floats around and intercepts myostatin and its relatives before they ever reach real muscle cells - acting like a decoy or a sponge. With fewer 'stop growing' signals getting through, muscle (and in animal studies, bone) grows faster.
Who should avoid it
- Anyone without direct medical supervision - this was always a monitored clinical-trial drug, never a self-administered product
- People with bleeding disorders or on blood-thinning medication, given the nosebleed signal seen in the human trial
- People with existing heart problems, given the heart-wall thickening seen in animal studies
- Pregnant or breastfeeding women - never studied in this group
- Children, outside of a formal, monitored clinical trial
- Competitive athletes - it is a banned substance under WADA anti-doping rules
- Anyone considering black-market 'ACE-031' products - lab testing has shown these are frequently mislabeled or contain a different, unproven protein entirely
Interactions to know
- No human drug-interaction studies exist for ACE-031
- The nosebleed and blood-vessel side effects seen in the DMD trial suggest caution combining it with blood thinners or other drugs that increase bleeding risk, though this hasn't been formally tested
- Effects on the heart seen in animal studies suggest it should not be combined with other drugs that also strain the heart without medical supervision
The papers that matter most
Key studies
The only real efficacy trial in patients. Showed hints of preserved muscle and walking ability, but the study was stopped early after nosebleeds and skin blood-vessel changes - the event that ended ACE-031's development.
Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial
Established the only human dosing and safety data that exists: a single 3 mg/kg shot measurably increased lean mass and thigh muscle volume within a month, with a 10-15 day half-life.
A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers
Confirmed the muscle-building effect in a primate, not just rodents, which is a stronger predictor of what might happen in humans.
ACE-031, a soluble activin type IIB receptor, increases muscle mass and strength in the common marmoset (Callithrix jacchus)
Found thickening of the heart's pumping wall after 12 weeks of treatment in monkeys - an important safety caution even though overall heart function wasn't clearly harmed in this short study.
Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques
Long-term blocking of this pathway in mice made muscle bigger but also weaker at the cellular energy level and quick to fatigue - a reminder that more muscle mass isn't automatically better function.
Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy
Tested 14 products sold online as ACE-031 - none actually contained the real drug, and 2 contained no relevant protein at all. Confirms that anything bought as 'ACE-031' outside a clinical trial is unverified and likely mislabeled.
Gel Electrophoretic Detection of Black Market ACE-031
Bottom line
ACE-031 reliably builds muscle in animals and showed the same signal in two small human trials, but its developer stopped the program in 2011 after patients had nosebleeds and skin blood-vessel changes, and it was never approved or picked up again. Treat it as a discontinued experimental drug with real safety red flags, not an available or verified product - anything sold under this name today has been shown in lab testing to often not even be the real thing.
Research papers
Studies we have on file for ACE-031. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy.
The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.
Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes.
Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDSs), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia; however, its molecular mechanism of action is unclear. We found that activin receptor 2B (ACVR2B), its ligand growth and differentiation factor 11 (GDF11), and an effector, SMAD2, are upregulated in samples of patients with MDS. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at the GATA1 intron. Intronic SMAD2-binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2-binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of GATA1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-Seq analysis of samples from the phase 3 MEDALIST trial revealed that responders to luspatercept had a higher proportion of GATA1s compared with nonresponders. Moreover, the increase in RBCs after treatment was linked to a relative decrease in GATA1s isoforms. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to luspatercept in MDS.
Gel Electrophoretic Detection of Black Market ACE-031.
The usage of ACE-031 (Ramatercept), a dimeric fusion protein consisting of a human activin receptor IIB (ACVR2B) fragment linked to an Fc-part of human IgG1, is banned according to chapter S4.3 of the "WADA 2024 List of Prohibited Substances and Methods" due to its potential performance enhancing properties. While ACE-031 has not yet been pharmaceutically approved, it is sold as research chemical on the "black market" (BM). The article presents a study on BM ACE-031 products and its detection by gel-electrophoresis and Western blotting. Of 14 tested products, only 12 contained an ACVR2B-immunoreactive protein. Electrophoretic separation by SDS-PAGE also showed that the 12 ACVR2B-products contained many other proteins in addition to the main compound (ca. 58.4 kDa). Further analyses by mass spectrometry and immunoblotting revealed that the 12 products contained the full-length human activin receptor IIB instead of ACE-031. The absence of an Fc-fusion protein was further confirmed by treatment with IdeS protease, which was unable to cleave the BM products. In addition, it was demonstrated that the protocol we developed to detect luspatercept (another ACVR2B-Fc fusion protein) in human serum could also be successfully applied for the detection of BM ACE-031. Because administering black market products to human subjects was not ethically justifiable, a study was conducted with rats. In rat serum, BM ACE-031 was detectable up to 48 h post administration. However, due to the relatively high dose applied (10 mg/kg body weight) and possible differences in metabolism, the detection window may be different in humans.
ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders.
Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.
Clinical Applications of Ligand Traps Targeting Activin Type II Receptors.
This review summarizes recent advances in ligand trap therapies targeting activin type II receptors [ActRIIA/ACVR2A and ActRIIB/ACVR2B], which serve as shared receptors for members of the TGF-β family, including activins, GDF11, and myostatin [MSTN]. These receptors mediate Smad2/3 signaling and play critical roles in hematopoiesis, vascular homeostasis, and muscle regulation. Two peptide-based ligand traps have recently received clinical approval: luspatercept [ActRIIB-Fc], an erythroid maturation agent, and sotatercept [ActRIIA-Fc], a novel therapeutic agent for pulmonary arterial hypertension [PAH]. Luspatercept primarily inhibits activin B and GDF11, thereby promoting late-stage erythropoiesis and demonstrating efficacy in anemia associated with conditions such as myelodysplastic syndromes [MDS] and β-thalassemia. Sotatercept binds activins and GDFs to rebalance Smad2/3 and Smad1/5/8 signaling, thereby improving vascular remodeling in PAH. Although both agents have failed to increase skeletal muscle mass in clinical trials consistently, they represent significant advances in the treatment of hematopoietic and vascular disorders. Future studies should focus on optimal dosing strategies, long-term safety, and potential synergistic effects when combined with other therapeutic modalities.
Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques.
An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two-dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety.
Gonadotropin elevation is ootoxic to ovulatory oocytes and inhibits oocyte maturation, and activin decoy receptor ActRIIB:Fc therapeutically restores maturation.
Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.
Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.
Most prostate cancers depend on androgens for growth, and therefore, the mainstay treatment for advanced, recurrent, or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty syndrome that includes fat gain and sarcopenia, defined as the loss of muscle function accompanied by reduced muscle mass or quality. Mice bearing Pten-deficient prostate cancers were examined to gain mechanistic insight into ADT-induced sarcopenic obesity. Castration induced fat gain as well as skeletal muscle mass and strength loss. Catabolic TGF-β family myokine protein levels were increased immediately prior to strength loss, and pan-myokine blockade using a soluble receptor (ActRIIB-Fc) completely reversed the castration-induced sarcopenia. The onset of castration-induced strength and muscle mass loss, as well as the increase in catabolic TGF-β family myokine protein levels, were coordinately accelerated in tumor-bearing mice relative to tumor-free mice. Notably, growth differentiation factor 11 (GDF11) increased in muscle after castration only in tumor-bearing mice, but not in tumor‑free mice. An early surge of GDF11 in prostate tumor tissue and in the circulation suggests that endocrine GDF11 signaling from tumor to muscle is a major driver of the accelerated ADT-induced sarcopenic phenotype. In tumor-bearing mice, GDF11 blockade largely prevented castration-induced strength loss but did not preserve muscle mass, which confirms a primary role for GDF11 in muscle function and suggests an additional role for the other catabolic myokines.
Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy.
Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.
GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting.
Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver-muscle negative crosstalk along with liver injury progression.
Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb.
The single transmembrane domain serine/threonine kinase activin receptor type IIB (ActRIIB) has been proposed to bind key regulators of skeletal muscle mass development, including the ligands GDF-8 (myostatin) and GDF-11 (BMP-11). Here we provide a detailed kinetic characterization of ActRIIB binding to several low and high affinity ligands using a soluble activin receptor type IIB-Fc chimera (ActRIIB.Fc). We show that both GDF-8 and GDF-11 bind the extracellular domain of ActRIIB with affinities comparable with those of activin A, a known high affinity ActRIIB ligand, whereas BMP-2 and BMP-7 affinities for ActRIIB are at least 100-fold lower. Using site-directed mutagenesis, we demonstrate that ActRIIB binds GDF-11 and activin A in different ways such as, for example, substitutions in ActRIIB Leu(79) effectively abolish ActRIIB binding to activin A yet not to GDF-11. Native ActRIIB has four isoforms that differ in the length of the C-terminal portion of their extracellular domains. We demonstrate that the C terminus of the ActRIIB extracellular domain is crucial for maintaining biological activity of the ActRIIB.Fc receptor chimera. In addition, we show that glycosylation of ActRIIB is not required for binding to activin A or GDF-11. Together, our findings reveal binding specificity and activity determinants of the ActRIIB receptor that combine to effect specificity in the activation of distinct signaling pathways.
Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.
Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.
Increased muscle force production and bone mineral density in ActRIIB-Fc-treated mature rodents.
Myostatin is a highly conserved member of the transforming growth factor-β ligand family known to regulate muscle growth via activation of activin receptors. A fusion protein consisting of the extracellular ligand-binding domain of activin type IIB receptor with the Fc portion of human immunoglobulin G (ActRIIB-Fc) was used to inhibit signaling through this pathway. Here, we study the effects of this fusion protein in adult, 18-month-old, and orchidectomized mice. Significant muscle growth and enhanced muscle function were observed in adult mice treated for 3 days with ActRIIB-Fc. The ActRIIB-Fc-treated mice had enhanced fast fatigable muscle function, with only minor enhancement of fatigue-resistant fiber function. The ActRIIB-Fc-treated 18-month-old mice and orchidectomized mice showed significantly improved muscle function. Treatment with ActRIIB-Fc also increased bone mineral density and serum levels of a marker of bone formation. These observations highlight the potential of targeting ActRIIB receptor to treat age-related and hypogonadism-associated musculoskeletal degeneration.
Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice.
In postmenopausal osteoporosis, hormonal changes lead to increased bone turnover and metabolic alterations including increased fat mass and insulin resistance. Activin type IIB receptors bind several growth factors of the TGF-β superfamily and have been demonstrated to increase muscle and bone mass. We hypothesized that ActRIIB-Fc treatment could improve bone and muscle mass, inhibit fat accumulation, and restore metabolic alterations in an ovariectomy (OVX) model of postmenopausal osteoporosis. Female C57Bl/6 N mice were subjected to SHAM or OVX procedures and received intraperitoneal injections of either PBS or ActRIIB-Fc (5 mg/kg) once weekly for 7 weeks. Glucose and insulin tolerance tests (GTT and ITT, respectively) were performed at 7 and 8 weeks, respectively. Bone samples were analyzed with micro-computed tomography imaging, histomorphometry, and quantitative RT-PCR. Bone mass decreased in OVX PBS mice compared to the SHAM PBS group but ActRIIB-Fc was able to prevent these changes as shown by µCT and histological analyses. This was due to decreased osteoclast numbers and function demonstrated by histomorphometric and qRT-PCR analyses. OVX induced adipocyte hypertrophy that was rescued by ActRIIB-Fc, which also decreased systemic adipose tissue accumulation. OVX itself did not affect glucose levels in GTT but ActRIIB-Fc treatment resulted in impaired glucose clearance in both SHAM and OVX groups. OVX induced mild insulin resistance in ITT but ActRIIB-Fc treatment did not affect this. Our results reinforce the potency of ActRIIB-Fc as a bone-enhancing agent but also bring new insight into the metabolic effects of ActRIIB-Fc in normal and OVX mice.
Gateways to clinical trials.
(-)-Epigallocatechin gallate, Abafungin, ACE-031, Adapalene/benzoyl peroxide, AE-37, Aflibercept, AGS-003, Albiglutide, Alemtuzumab, Aliskiren fumarate, ALT-801, AN-2728, Anacetrapib, API, Aprepitant, ARQ-197, Ascorbic acid, Atazanavir sulfate, ATN-224, AVI-4658, Azacitidine, Azelnidipine; Belinostat, Bevacizumab, BI-2536, Biphasic insulin aspart, Bortezomib, Bovine lactoferrin, Bryostatin 1, Budesonide/formoterol fumarate; cAC10, Canfosfamide hydrochloride, Cediranib, Clofarabine, Cocaine conjugate vaccine; Darbepoetin alfa, Dasatinib, Denosumab, Disomotide, Doripenem, Dovitinib Lactate, Dronedarone hydrochloride, Drospirenone/estradiol, Dutasteride; Ecogramostim, Entinostat, Enzastaurin hydrochloride, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fampridine, Fenretinide LXS, FFR-factor VIIa, Fingolimod hydrochloride, Frovatriptan; Gefitinib, Gimatecan, GP-2/GM-CSF; Iloperidone, Imatinib mesylate, Indibulin, Ipilimumab, Ivabradine hydrochloride; Lactobacillus rhamnosus, Lapatinib ditosylate, LC-07, Lenalidomide, Linifanib, Liposomal doxorubicin, Liposomal vincristine, Litenimod, Lutein; M-118, MDX-1401, MEDI-528, Midostaurin, Miglustat, MK-0657; Natalizumab, Nesiritide, NGR-TNF, Niacin/simvastatin; Obatoclax mesylate, Olaparib, Omacetaxine mepesuccinate; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Palonosetron hydrochloride, Pazopanib hydrochloride, Pegfilgrastim, Pemetrexed disodium, PER.C-flu, Perifosine, PF-02341066, Pimecrolimus, Pitrakinra, Plerixafor hydrochloride, Posaconazole; Rasburicase, Recombinant human relaxin H2, ReoT3D, Retaspimycin hydrochloride, Riferminogene pecaplasmid, Rindopepimut, Romiplostim, Ronacaleret hydrochloride, Rosuvastatin calcium, Rotigotine; Sagopilone, sALP-FcD10, SAR-245409, SCH-697243, Selumetinib, Sirolimus-eluting stent, SIR-Spheres, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tandutinib, Tasimelteon, Temsirolimus, Teriparatide, Tiotropium bromide, TIV, Trabectedin, Tremelimumab, TRU-016; Vadimezan, Val8-GLP-1(7-37)OH, Vandetanib, Vernakalant hydrochloride, Voreloxin, Voriconazole, Vorinostat, Yttrium 90 (90Y) ibritumomab tiuxetan; Zeaxanthin, Ziprasidone hydrochloride, Zosuquidar trihydrochloride.
Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size.
Myostatin, a member of the TGF-β superfamily, is a negative regulator of skeletal muscle cell growth and differentiation, and binds with high affinity to the activin type IIB receptor (ActRIIB). The soluble ligand-binding domain of ActRIIB fused to the Fc domain of IgG (ActRIIB-Fc) potently binds and inhibits TGF-β family members in muscle, leading to rapid and marked muscle growth. The present study was designed to assess the effectiveness of the co-delivery of myostatin-targeting siRNA (Mstn-siRNA) and ActRIIB-Fc into skeletal muscle as a potential treatment of atrophic myopathies. Eleven-week-old, male C57BL/6 mice were injected with atelocollagen (ATCOL)-mediated Mstn-siRNA with/without ActRIIB-Fc locally into the masseter muscle twice a week. Inhibition of myostatin function by the combination of Mstn-siRNA and ActRIIB-Fc increased muscle weight and myofibril size in murine masseter muscle. Real-time RT-PCR analysis revealed significant downregulation of myostatin mRNA expression in both the Mstn-siRNA-treated and the combination treatment group. Furthermore, myogenin mRNA expression was upregulated in the combination treatment group, while MuRF-1 and Atrogin-1 mRNA expression was downregulated compared to administration of each compound alone. These findings suggest that double inhibition of myostatin is a potentially useful treatment strategy to increase muscle mass and fiber size and could be a useful treatment of patients with various muscle atrophies, including muscular dystrophy.
Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.
Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.
[Anti-myostatin antibody therapy for myopathies].
Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β family, negatively regulates skeletal muscle growth. It inhibits muscle stem cell proliferation and differentiation, and attenuates adult muscle fiber protein accretion, resulting in decreased skeletal muscle mass. Thus it has been considered to be a therapeutic target of myopathies including muscular dystrophy. Notably, administration of a blocking antibody against myostatin ameliorated the pathophysiology of dystrophin-deficient mdx mice. Although a clinical trial of an anti-myostatin antibody MYO-029 failed to achieve a significant outcome in patients with muscular dystrophies, various distinct approaches have been taken to establish anti-myostatin therapy including a myostatin decoy receptor ACE-031, a peptide drug derived from myostatin prodomain, small-molecule inhibitors against the myostatin receptor, a follistatin-derived peptibody inhibiting myostatin and myostatin siRNA with collagen-derived carrier particles. Clinical application of the anti-myostatin therapeutics for the treatment of patients with muscular dystrophy needs further evaluation of safety and specification of the target disease types among various muscular dystrophies.
ACE-031, a soluble activin type IIB receptor, increases muscle mass and strength in the common marmoset (Callithrix jacchus).
Pharmacological blockade of ligands for the activin receptor type IIB (ActRIIB) e.g., myostatin and activin A is associated with improvements in murine skeletal muscle mass and function. The efficacy of a similar treatment approach in a non-human primate (NHP) model would suggest a greater likelihood of success in the treatment of humans suffering from chronic myopathies. In the present study, we elucidate the potential therapeutic benefit of ACE-031, a therapeutic protein consisting of the ActRIIB extracellular region fused to human IgG1, in the common marmoset (Callithrix jacchus). Marmosets were randomized to receive ACE-031 or vehicle control (10 mM Tris buffered saline; TBS) for 14 weeks. Body composition was measured weekly throughout the experimental period and morphometric analysis and contractile properties of skeletal muscle were assessed terminally. There was a significant main effect of time and time x treatment interaction for lean body mass, such that marmosets administered ACE-031 were greater at euthanasia compared to baseline; this was not observed in the vehicle-treated controls. Biceps brachii exhibited a significant increase in the cross-sectional area of both type I and type II fibers and ex vivo contractile properties of the EDL showed an increase in absolute and specific force production. The efficacy of ACE-031 in non-human primates provides optimism that a therapeutic strategy that targets multiple negative regulators of skeletal muscle may be beneficial in treating myopathies in humans.
Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle.
Follistatin is an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor-β superfamily and may therefore have therapeutic potential for neuromuscular diseases. Here, we sought to determine the suitability of a newly engineered follistatin fusion protein (FST288-Fc) to promote localized, rather than systemic, growth of skeletal muscle by capitalizing on the intrinsic heparin-binding ability of the follistatin-288 isoform. As determined by surface plasmon resonance and cell-based assays, FST288-Fc binds to activin A, activin B, myostatin (growth differentiation factor GDF8), and GDF11 with high affinity and neutralizes their activity in vitro. Intramuscular administration of FST288-Fc in mice induced robust, dose-dependent growth of the targeted muscle but not of surrounding or contralateral muscles, in contrast to the systemic effects of a locally administered fusion protein incorporating activin receptor type IIB (ActRIIB-Fc). Furthermore, systemic administration of FST288-Fc in mice did not alter muscle mass or body composition as determined by NMR, which again contrasts with the pronounced systemic activity of ActRIIB-Fc when administered by the same route. Subsequent analysis revealed that FST288-Fc in the circulation undergoes rapid proteolysis, thereby restricting its activity to individual muscles targeted by intramuscular administration. These results indicate that FST288-Fc can produce localized growth of skeletal muscle in a targeted manner with reduced potential for undesirable systemic effects. Thus, FST288-Fc and similar agents may be beneficial in the treatment of disorders with muscle atrophy that is focal, asymmetric, or otherwise heterogeneous.
Combined detection of the ActRII-Fc fusion proteins Sotatercept (ActRIIA-Fc) and Luspatercept (modified ActRIIB-Fc) in serum by means of immunoaffinity purification, tryptic digestion, and LC-MS/MS.
Therapeutic proteins are a continuously growing class of pharmaceuticals and comprise several drug candidates with potential performance-enhancing properties. In particular, activin receptor competitors, such as the ActRII-Fc fusion proteins Sotatercept (ActRIIA-Fc) and Luspatercept (modified ActRIIB-Fc), have the potential for being misused as doping agents in sports as they were found to inhibit negative regulators of late-stage erythropoiesis. Within this study, ammonium sulfate precipitation, immunoaffinity purification, tryptic digestion, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were employed to develop an assay for the combined detection of Sotatercept and Luspatercept in doping control serum samples. The assay was optimized, comprehensively characterized, and found to be fit-for-purpose for application to sports drug testing. It complements existing tests for ActRII-Fc fusion proteins and expands the range of available detection methods for novel protein therapeutics.
Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial.
ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017.
The effects of an ActRIIb receptor Fc fusion protein ligand trap in juvenile simian immunodeficiency virus-infected rhesus macaques.
There are no approved therapies for muscle wasting in children infected with human immunodeficiency virus (HIV), which portends poor disease outcomes. To determine whether a soluble ActRIIb receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, can prevent or restore loss of lean body mass and body weight in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239 and, 4 wk postinoculation (WPI) treated with intramuscular injections of 10 mg ⋅ kg(-1) ⋅ wk(-1) ActRIIB.Fc or saline placebo. Body weight, lean body mass, SIV titers, and somatometric measurements were assessed monthly for 16 wk. Age-matched SIV-infected rhesus macaques were injected with saline. Intervention groups did not differ at baseline. Gains in lean mass were significantly greater in the ActRIIB.Fc group than in the placebo group (P < 0.001). Administration of ActRIIB.Fc was associated with greater gains in body weight (P = 0.01) and upper arm circumference than placebo. Serum CD4(+) T-lymphocyte counts and SIV copy numbers did not differ between groups. Administration of ActRIIB.Fc was associated with higher muscle expression of myostatin than placebo. ActRIIB.Fc effectively blocked and reversed loss of body weight, lean mass, and fat mass in juvenile SIV-infected rhesus macaques.
RKER-012, a modified ActRIIB-Fc ligand trap with BMP sparing properties, attenuates pathological features of experimental pulmonary arterial hypertension.
Overactive activin/growth and differentiation factor (GDF) signaling is one of the many pathogenic drivers of progressive vascular remodeling and right ventricular (RV) failure in pulmonary arterial hypertension (PAH). In contrast, bone morphogenic proteins (BMPs) play a crucial role in maintaining vascular homeostasis. The clinical success of sotatercept, an activin receptor (ActR)IIA-Fc ligand trap, has paved the way for targeting activin/GDF signaling in PAH. However, sotatercept has limitations, including severe thrombocytopenia and erythrocytosis, which may increase the risk of hyperviscosity syndrome (HVS) and bleeding. Here, we demonstrated that a modified ActRIIB-Fc ligand trap, KER-012/RKER-012, exhibited BMP-sparing properties while retaining binding to activin/GDF ligands, similar to the wild-type ActRIIA and ActRIIB ligand traps. We also demonstrated that hypoxia increased susceptibility to HVS-related bleeding and mortality in response to erythropoietin (EPO)-induced erythrocytosis and severe thrombocytopenia in Sugen rats. Unlike sotatercept, KER-012/RKER-012 did not elicit erythrocytosis or thrombocytopenia; therefore, a modified ActRIIB-Fc ligand trap like KER-012/RKER-012 could reduce the risk of potential HVS effect and bleeding. We also showed that RKER-012 can attenuate experimental PAH by targeting multiple components of a complex pathobiology, such as dysregulated cell growth, endothelial-to-mesenchymal transition (EndoMT), extracellular matrix (ECM) remodeling, inflammation, immune cell modulation, and fibrosis. This evidence highlights the potential to optimize an activin receptor ligand trap to target overactive activin/GDF signaling in PAH while sparing BMP signaling and minimizing the risk of bleeding, vascular integrity, and erythrocytosis. Ultimately, this approach could improve pulmonary vascular remodeling to alleviate PAH.
A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers.
ACE-031 is a soluble form of activin receptor type IIB (ActRIIB). ACE-031 promotes muscle growth by binding to myostatin and other negative regulators of muscle mass. This double-blind, placebo-controlled study evaluated the safety, pharmacokinetics, and pharmacodynamics of ACE-031 in 48 healthy, postmenopausal women randomized to receive 1 dose of ACE-031 (0.02-3 mg/kg s.c.) or placebo (3:1). ACE-031 was generally well-tolerated. Adverse events included injection site erythema. Mean ACE-031 AUC(0-∞) and C(max) increased linearly with dose; mean T(½) was 10-15 days. Statistically significant increases in mean total body lean mass (3.3%; P = 0.03, by DXA) and thigh muscle volume (5.1%; P = 0.03, by MRI) were observed at day 29 in the 3 mg/kg group. Statistically significant changes in serum biomarkers suggest ACE-031 also improved bone and fat metabolism. Single-dose ACE-031 treatment was generally well-tolerated and resulted in increases in muscle mass in healthy postmenopausal women.
Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection.
Activin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB patients compared to healthy controls, including those with positive tuberculin skin tests, and paralleled severity of disease, assessed by X-ray scores. In pneumonia patients, serum activin A levels were also raised, but in sarcoidosis patients, levels were lower. To determine whether blockade of the activin A signaling axis could play a functional role in TB, we harnessed a soluble activin type IIB receptor fused to human IgG1 Fc, ActRIIB-Fc, as a ligand trap in a murine TB model. The administration of ActRIIB-Fc to Mycobacterium tuberculosis-infected mice resulted in decreased bacterial loads and increased numbers of CD4 effector T cells and tissue-resident memory T cells in the lung. Increased frequencies of tissue-resident memory T cells corresponded with downregulated T-bet expression in lung CD4 and CD8 T cells. Altogether, the results suggest a disease-exacerbating role of ActRIIB signaling pathways. Serum activin A may be useful as a biomarker for diagnostic triage of active TB or monitoring of anti-tuberculosis therapy. Tuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, Mycobacterium tuberculosis, can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to Mycobacterium tuberculosis and activin A as a biomarker of ongoing disease.
The relationship between myodural bridges, hyperplasia of the suboccipital musculature, and intracranial pressure.
During mammalian evolution, the Myodural Bridges (MDB) have been shown to be highly conserved anatomical structures. However, the putative physiological function of these structures remains unclear. The MDB functionally connects the suboccipital musculature to the cervical spinal dura mater, while passing through the posterior atlanto-occipital and atlanto-axial interspaces. MDB transmits the tensile forces generated by the suboccipital muscles to the cervical dura mater. Moreover, head movements have been shown to be an important contributor to human CSF circulation. In the present study, a 16-week administration of a Myostatin-specific inhibitor, ACE-031, was injected into the suboccipital musculature of rats to establish an experimental animal model of hyperplasia of the suboccipital musculature. Using an optic fiber pressure measurement instrument, the present authors observed a significant increase in intracranial pressure (ICP) while utilizing the hyperplasia model. In contrast, surgically severing the MDB connections resulted in a significant decrease in intracranial pressure. Thus, these results indicated that muscular activation of the MDB may affect CSF circulation, suggesting a potential functional role of the MDB, and providing a new research perspective on CSF dynamics.
A myostatin and activin decoy receptor enhances bone formation in mice.
Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass. To investigate the role of myostatin in bone, young adult mice were administered with either a myostatin neutralizing antibody (Mstn-mAb), a soluble myostatin decoy receptor (ActRIIB-Fc) or vehicle. While both myostatin inhibitors increased muscle mass, only ActRIIB-Fc increased bone mass. Bone volume fraction (BV/TV), as determined by microCT, was increased by 132% and 27% in the distal femur and lumbar vertebrae, respectively. Histological evaluation demonstrated that increased BV/TV in both locations was attributed to increased trabecular thickness, trabecular number and bone formation rate. Increased BV/TV resulted in enhanced vertebral maximum compressive force compared to untreated animals. The fact that ActRIIB-Fc, but not Mstn-mAb, increased bone volume suggested that this soluble decoy receptor may be binding a ligand other than myostatin, that plays a role in regulating bone mass. This was confirmed by the significant increase in BV/TV in myostatin deficient mice treated with ActRIIB-Fc. Of the other known ActRIIB-Fc ligands, BMP3 has been identified as a negative regulator of bone mass. However, BMP3 deficient mice treated with ActRIIB-Fc showed similar increases in BV/TV as wild type (WT) littermates treated with ActRIIB-Fc. This result suggests that BMP3 neutralization is not the mechanism responsible for increased bone mass. The results of this study demonstrate that ActRIIB-Fc increases both muscle and bone mass in mice. Therefore, a therapeutic that has this dual activity represents a potential approach for the treatment of frailty.
ACE-031, a Soluble Activin Type IIB Receptor, Increases Muscle Mass and Strength in the Common Marmoset (Callithrix jacchus).
Pharmacological blockade of ligands for the activin receptor type IIB (ActRIIB) e.g., myostatin and activin A is associated with improvements in murine skeletal muscle mass and function. The efficacy of a similar treatment approach in a non-human primate (NHP) model would suggest a greater likelihood of success in the treatment of humans suffering from chronic myopathies. In the present study, we elucidate the potential therapeutic benefit of ACE-031, a therapeutic protein consisting of the ActRIIB extracellular region fused to human IgG1, in the common marmoset (Callithrix jacchus). Marmosets were randomized to receive ACE-031 or vehicle control (10 mM Tris buffered saline; TBS) for 14 weeks. Body composition was measured weekly throughout the experimental period and morphometric analysis and contractile properties of skeletal muscle were assessed terminally. Marmosets administered ACE-031 showed a significant increase in body weight and lean body mass from baseline, while no change was seen in the vehicle-treated controls. Biceps brachii exhibited a significant increase in the cross-sectional area of both type I and type II fibers and ex vivo contractile properties of the EDL showed an increase in absolute and specific force production. The efficacy of ACE-031 in non-human primates provides optimism that a therapeutic strategy that targets multiple negative regulators of skeletal muscle may be beneficial in treating myopathies in humans.
A novel therapeutic approach to treating obesity through modulation of TGFβ signaling.
Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.
Advances in understanding and treating cardiac cachexia: highlights from the 5th Cachexia Conference.
Cardiac cachexia as a terminal stage of chronic heart failure carries a devastating prognosis. This article focuses on novel insights into the pathophysiology and on new treatment approaches to cardiac cachexia. Drugs that have been used in preclinical and clinical studies that may also confer beneficial effects in cardiac cachexia include but are not limited to the type 4 melanocortin receptor antagonist SNT 207979, the appetite promoting synthetic ghrelin SUN11031, the soluble myostatin decoy receptor ActRIIB-Fc, the fast skeletal muscle troponin activating substance CK-2017357, the anti-catabolic/anabolic transforming agent MT-102, the anti-inflammatory agent celecoxib, and testosterone supplementation.
Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy.
Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD. Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks. Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice. Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.
The soluble form of BMPRIB is a novel therapeutic candidate for treating bone related disorders.
Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the TGF-beta superfamily. Recently, several soluble BMP receptors, such as ActRIIA-Fc, ActRIIB-Fc, and ALK1-Fc, are undergoing clinical trials. Both BMPRIA and BMPRIB are type I BMP receptors, and while BMPRIA-Fc has been reported to have bone-increasing properties, there have been no investigations concerning the biological functions of BMPRIB-Fc. Therefore, comparing the effects of BMPRIA-Fc and BMPRIB-Fc in vivo should be helpful in revealing the differences in biological function between BMPRIA and BMPRIB, and would also aid in the evaluation of BMPRIB-Fc as a therapeutic agent. Here, we produced Tg chimeras in which BMPRIA-Fc and BMPRIB-Fc proteins circulated at high concentrations (36.8-121.4 μg/mL). Both Tg chimeras showed a significant increase of bone volume and strength. Using histological analysis, adenoma of the glandular stomach was observed only in BMPRIA-Fc chimeras suggesting the tumorigenic activity of this protein. Administration of recombinant BMPRIB-Fc protein to normal mice also increased bone volumes. Finally, treatment with BMPRIB-Fc decreased the area of osteolytic regions in a mouse model of breast cancer metastasis. In conclusion, our data suggest that BMPRIB-Fc can be used for the treatment of bone-related disorders with a lower risk than BMPRIA-Fc.
The relationship between myodural bridge, atrophy and hyperplasia of the suboccipital musculature, and cerebrospinal fluid dynamics.
The Myodural Bridge (MDB) is a physiological structure that is highly conserved in mammals and many of other tetrapods. It connects the suboccipital muscles to the cervical spinal dura mater (SDM) and transmits the tensile forces generated by the suboccipital muscles to the SDM. Consequently, the MDB has broader physiological potentials than just fixing the SDM. It has been proposed that MDB significantly contributes to the dynamics of cerebrospinal fluid (CSF) movements. Animal models of suboccipital muscle atrophy and hyperplasia were established utilizing local injection of BTX-A and ACE-031. In contrast, animal models with surgical severance of suboccipital muscles, and without any surgical operation were set as two types of negative control groups. CSF secretion and reabsorption rates were then measured for subsequent analysis. Our findings demonstrated a significant increase in CSF secretion rate in rats with the hyperplasia model, while there was a significant decrease in rats with the atrophy and severance groups. We observed an increase in CSF reabsorption rate in both the atrophy and hyperplasia groups, but no significant change was observed in the severance group. Additionally, our immunohistochemistry results revealed no significant change in the protein level of six selected choroid plexus-CSF-related proteins among all these groups. Therefore, it was indicated that alteration of MDB-transmitted tensile force resulted in changes of CSF secretion and reabsorption rates, suggesting the potential role that MDB may play during CSF circulation. This provides a unique research insight into CSF dynamics.
[Myostatin blockade therapy for muscular atrophy].
Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β family, negatively regulates skeletal muscle growth. It inhibits muscle stem cell proliferation and differentiation and attenuates adult muscle fiber protein accretion, resulting in decreased skeletal muscle mass. As such, it has been considered a therapeutic target of muscular dystrophy. Notably, administration of a blocking antibody against myostatin ameliorated the pathophysiology of dystrophin-deficient mdx mice. Although a clinical trial of anti-myostatin antibody MYO-029 failed to achieve a significant outcome in patients with muscular dystrophies, various distinct approaches have been taken to establish anti-myostatin therapy, including myostatin decoy receptor ACE-031, small-molecule inhibitors against the myostatin receptor, and myostatin short intertering RNA with collagen-derived carrier particles. The clinical application of anti-myostatin therapeutics in treatment of patients with muscular dystrophy needs further evaluation for safety and specification of the target disease types among the various muscular dystrophies. In addition, myostatin inhibition could be effective for muscle-wasting conditions other than muscular dystrophy- for instance, steroid-induced myopathy, mitochondrial myopathy, or sarcopenia in elderly patients. Moreover, considerable evidence shows that myostatin regulates energy metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. It may also be applicable for the prevention of metabolic syndrome. Thus, safe and potent anti-myostatin therapy will have a wide variety of applications in modern medicine.
Soluble activin type IIB receptor improves fracture healing in a closed tibial fracture mouse model.
Fractures still present a significant burden to patients due to pain and periods of unproductivity. Numerous growth factors have been identified to regulate bone remodeling. However, to date, only the bone morphogenetic proteins (BMPs) are used to enhance fracture healing in clinical settings. Activins are pleiotropic growth factors belonging to the TGF-β superfamily. We and others have recently shown that treatment with recombinant fusion proteins of activin receptors greatly increases bone mass in different animal models by trapping activins and other ligands thus inhibiting their signaling pathways. However, their effects on fracture healing are less known. Twelve-week old male C57Bl mice were subjected to a standardized, closed tibial fracture model. Animals were divided into control and treatment groups and were administered either PBS control or a soluble activin type IIB receptor (ActRIIB-Fc) intraperitoneally once a week for a duration of two or four weeks. There were no significant differences between the groups at two weeks but we observed a significant increase in callus mineralization in ActRIIB-Fc-treated animals by microcomputed tomography imaging at four weeks. Bone volume per tissue volume was 60%, trabecular number 55% and bone mineral density 60% higher in the 4-week calluses of the ActRIIB-Fc-treated mice (p<0.05 in all). Biomechanical strength of 4-week calluses was also significantly improved by ActRIIB-Fc treatment as stiffness increased by 64% and maximum force by 45% (p<0.05) compared to the PBS-injected controls. These results demonstrate that ActRIIB-Fc treatment significantly improves healing of closed long bone fractures. Our findings support the previous reports of activin receptors increasing bone mass but also demonstrate a novel approach for using ActRIIB-Fc to enhance fracture healing.
Inhibition of myostatin reverses muscle fibrosis through apoptosis.
Skeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibition of myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc) reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existing muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.
Detection of activin receptor type IIA and IIB-Fc fusion proteins by automated capillary immunoassay.
Activin receptor type IIA and type IIB fusion protein have been designed to sequester circulating molecules of the transforming growth factor-β (TGF-β) superfamily and inactivate their actions. Members of this superfamily have been reported as essential regulators of erythropoiesis by triggering the formation of activated ternary complexes containing different combinations of type I and type II receptors, which can limit RBC production by accelerating erythroid differentiation and inhibiting erythroid progenitor expansion. The recent approval of Luspatercept for the treatment of anemia associated to transfusion-dependent MDS and Beta-thalassemia in afflicted patients means that it can now pose a real threat of being abused in sport for its ability to stimulate erythropoiesis. Several methods for the detection of these molecules in blood have been proposed for the purpose of sport antidoping control. Here we propose the detection of the ActRIIA-Fc and ActRIIB-Fc fusion proteins by automated capillary Western immunoassay (Simple Western). The use of these immunoassays for the detection of protein targets has become widespread in the recent years. The work presented here demonstrates that this methodology enables a versatile, rapid, and sensitive detection of activin ligand traps in blood samples: plasma, serum, or dried blood spots (DBS). Preliminary results indicate that detection in urine samples is also possible. The option to use different antibodies allows the possibility to use this method as an initial testing procedure as well as a confirmation procedure. Finally, results coming from an administration study confirm that the method is suitable for routine analysis.
Activin A contributes to the development of hyperoxia-induced lung injury in neonatal mice.
Bronchopulmonary dysplasia (BPD) is one of the leading causes of morbidity and mortality in babies born prematurely, yet there is no curative treatment. In recent years, a number of inhibitors against TGFβ signaling have been tested for their potential to prevent neonatal injury associated with hyperoxia, which is a contributing factor of BPD. In this study, we assessed the contribution of activin A-a member of the TGFβ superfamily-to the development of hyperoxia-induced lung injury in neonatal mice. We placed newborn C57Bl6 mouse pups in continuous hyperoxia (85% O2) to mimic many aspects of BPD including alveolar simplification and pulmonary inflammation. The pups were administered activin A receptor type IIB-Fc antagonist (ActRIIB-Fc) at 5 mg/kg or follistatin at 0.1 mg/kg on postnatal days 4, 7, 10, and 13. Treatment with ActRIIB-Fc and follistatin protected against hyperoxia-induced growth retardation. ActRIIB-Fc also reduced pulmonary leukocyte infiltration, normalized tissue: airspace ratio and increased septal crest density. These findings were associated with reduced phosphorylation of Smad3 and decreased matrix metalloproteinase (MMP)-9 activity. This study suggests that activin A signaling may contribute to the pathology of bronchopulmonary dysplasia.
Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss.
HIV-infected individuals are at an increased risk of osteoporosis despite effective viral suppression. Observations that myostatin null mice have increased bone mass led us to hypothesize that simian immunodeficiency virus (SIV)-associated bone loss may be attenuated by blocking myostatin/TGFβ signaling. In this proof-of-concept study, pair-housed juvenile male rhesus macaques were inoculated with SIVmac239. Four weeks later, animals were treated with vehicle or Fc-conjugated soluble activin receptor IIB (ActR2B·Fc, iv. 10mg∗kg-1∗week-1) - an antagonist of myostatin and related members of TGFβ superfamily. Limb and trunk bone mineral content (BMC) and density (BMD) using dual-energy X-Ray absorptiometry, circulating markers of bone growth and turnover, and serum testosterone levels were measured at baseline and during the 12-week intervention period. The increase in BMC was significantly greater in the ActRIIB.Fc-treated group (+8g) than in the placebo group (-4g) (p<0.05). BMD also increased significantly more in the ActRIIB.Fc-treated macaques (+0.03g/cm2) than in the placebo-treated animals (+0g/cm2) (p<0.005). Serum osteocalcin was about two-fold higher in the ActRIIB.Fc-treated group than in the placebo group (p<0.05), but serum C-terminal telopeptide and testosterone levels did not differ significantly between groups. The expression levels of TNFalpha (p<0.05), GADD45 (p<0.005), and sclerostin (p<0.038) in the bone-marrow were significantly lower in the ActRIIB.Fc-treated group than in the placebo group. The administration of ActRIIB.FC in SIV-infected juvenile macaques significantly increases BMC and BMD in association with reduced expression levels of markers of bone marrow inflammation.
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