don't know if I am allowed but I'll try...
ACE-031 is a novel, muscle-building agent that is being developed for the treatment of patients with Duchenne Muscular Dystrophy with the goal of improving strength and preserving physical function.
What is ACE-031?
ACE-031 is an investigational protein therapeutic that builds muscle and increases strength by inhibiting molecules that bind to and signal through a cell surface receptor called Activin Receptor Type IIB (ActRIIB). ACE-031 is a recombinant fusion protein that is produced by joining a portion of the human ActRIIB receptor to a portion of a human antibody. This creates a freely circulating, decoy version of ActRIIB which removes proteins, such as GDF-8 (myostatin) and other related molecules that limit the growth and strength of muscle.
The Role of ActRIIB Signaling and Muscle Growth
Muscle growth is regulated by proteins in the TGF-β protein superfamily that serve as “on” or “off” switches for muscle production. Several molecules including GDF-8 interact with the ActRIIB receptor and send an “off” signal to stop muscle production. In the absence of these “off” switch molecules that signal through the ActRIIB receptor, muscle mass increases dramatically.
Decreased ActRIIB Signaling Results in Muscle Growth
In nature, this effect has been observed in numerous species, particularly in animals that have been bred for increased musculature and strength. For example, Belgian Blue cattle lack the gene for GDF-8, which is one of several molecules that activate the ActRIIB receptor. A deficiency of this protein results in cattle with tremendously developed musculature and strength. Similar effects have been observed in other species, including rodents, dogs and even humans.
Treatment with ACE-031 Builds Skeletal Muscle
Treatment with ACE-031 promotes muscle growth by inhibiting ActRIIB signaling. ACE-031 binds to proteins that signal through the ActRIIB receptor to limit muscle growth. When ACE-031 binds to these proteins, it prevents them from interacting with the ActRIIB receptor, thus allowing muscle to grow. Moreover, because ACE-031 prevents GDF-8 and other proteins that regulate muscle mass from signaling through the ActRIIB receptor, its effects on lean muscle exceed those of inhibitors of GDF-8 (myostatin) alone.
Non-Clinical Results:
When animals are treated with ACE-031, they experience growth in lean muscle and are considerably stronger than their untreated counterparts. This has been shown in several species, and in both healthy animals and in animals with diseases associated with muscle weakness and wasting.
Clinical Results:
Single Ascending Dose Phase 1 Study - Acceleron completed a clinical study of ACE-031 (A031-01) in 48 healthy postmenopausal women. These subjects received a single dose of ACE-031 across a range of dose levels. For a description of the study design, click here. For the poster presentation of the study results click here and click here for the accompanying press release.
At higher doses, the effects of ACE-031 on skeletal muscle were encouraging. After a single dose of ACE-031, subjects developed roughly 1 kilogram (over 2 pounds) of muscle at 2 weeks. Moreover, ACE-031 altered biomarkers of fat metabolism (increased adiponectin and decreased leptin) and bone formation and resorption (increased BSAP and decreased CTX) at single doses of 1 and 3 mg/kg.
ACE-031 was generally well-tolerated at all dose levels. No serious adverse events were observed. The majority of adverse events were mild and transient.
Multiple Ascending Dose Phase 1 Study - A study in healthy postmenopausal women (A031-02), evaluating multiple doses of ACE-031, is currently ongoing. For more information on the study design, click here. Acceleron has presented preliminary results from this study. Click here for the poster presentation of these results and click here for the accompanying press release. As this study is not complete, final results are not yet available.
A031-02 randomized 60 subjects in 6 cohorts of 10 subjects each to receive ACE-031 or placebo (8:2) at dose levels ranging from 0.1 to 3 mg/kg given by SC injection every two or four weeks for a total of three or two doses, respectively, over a four week period. Subjects were followed for 12 weeks after their last dose. Although this safety study was not powered to assess statistically significant changes in endpoints, multiple exploratory statistical analyses were performed on the data.
Consistent with the findings of the single dose study (A031-01), multiple doses of ACE-031 given to healthy postmenopausal women were generally well tolerated and resulted in rapid and sustained effects on muscle, bone and fat. The most common adverse events were injection site reactions, headache and nosebleeds. The majority of adverse events were mild and transient. ACE-031 had a half-life of approximately 12 days, supportive of dosing every 2-4 weeks.
Mean total body lean mass measured by DXA at day 36 increased by 5.2% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks. This was statistically significant compared to the 0.4% increase in the placebo group (p=0.008) and was sustained through day 57. Significant increases were also seen at doses of 2 and 3 mg/kg every 4 weeks.
Mean thigh muscle volume measured by MRI at day 36 increased by 4.1% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks compared to 1.1% in the placebo group (p=0.012). Significant increases were also seen at 2 mg/kg given every 4 weeks. No statistically significant changes were observed in grip strength or functional tests in this healthy volunteer safety study.
Total Whole Body Lean Body Mass (DXA)
% Change (Mean +/- SE)
Thigh Muscle Volume (MRI)
% Change (Mean +/- SE)
ACE-031 treatment led to a rapid and significant increase in a biomarker of bone formation (BSAP) and decrease in a biomarker of bone resorption (CTX) versus placebo. Consistent with these effects, lumbar spine bone mineral density by DXA increased up to 3.4% in the 2 mg/kg every 4 week group from baseline to day 113, compared with a decrease of 1.5% in the placebo group (p=0.001).
ACE-031 treatment also led to significantly altered biomarkers of fat metabolism (increased adiponectin and decreased leptin) by day 8. Total body fat mass measured by DXA decreased up to 8.2% from baseline at day 113 in the 3 mg/kg every 4 week group compared with an increase of 0.5% in the placebo group (p=0.024).
Acceleron is developing ACE-031 for the treatment of patients with neuromuscular diseases, such as Duchenne Muscular Dystrophy (DMD), with the goal of improving strength and preserving physical function. By affecting the muscle directly, ACE-031 may one day offer hope to patients suffering from these debilitating diseases.
References
A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs, Mosher DS et al. PLoS Genet 3(5): e79, 2007.
Regulation of muscle growth by multiple ligands signaling through activin type II receptors, Lee SJ et. al., PNAS 102:18117-18122, 2005.
Inhibition of myostatin in adult mice increases skeletal muscle mass and strength, Whittemore LA et al., Biochem Biophys Res Commun. 2003 Jan 24;300(4):965-71.
Regulation of myostatin activity and muscle growth, Lee SJ et. al., PNAS, 98:9306-9311, 2001.
Our Recommended Dosage
Inject 1ml bacteriostatic water into vial
Draw out 1iu per day and inject bilaterally at growth site
Intramuscular
OR
Draw out 5iu on day 1 and inject bilaterally at growth site
Intramuscular.
Then another 5iu on day 5 and inject bilaterally at growth site
Intramuscular.
ACVR2B (ACE-031)
Weird name huh? What’s weirder is how its made.
What is It?
ACVR2B (ACE-031) has to be the coolest and strangest thing out there. It is a monoclonal antibody genetically engineered to bind to myostatin before myostatin can bind to its receptor and stop muscle growth.
What is Myostatin and Why Stop It?
I have already covered this in detail in my myostatin article. (the word myostatin is red because it is a hyperlink, click on it to learn more about myostatin.)
Simple simple simple version: Myostatin tells muscle cells to not grow and not to replicate. Blocking myostatin will help muscles get bigger, to date there has been only Follistatin that is widely used to block myostatin.
How is it made?
This is how bad people want to stop myostatin, to simply run an experiment this is what they had to do:
1) Take a portion of human DNA that had the genes necessary to code for JUST THE TIP of the myostatin receptor, not the whole thing, just the tip. This was the part that binds to the myostatin protein.
2) Ran a polymerase chain reaction to amplify this gene fragment, but not before they added genetic code so that the digestive enzymes would cut at the precise right location on this synthesized DNA.
3) The new gene, the tip of the myostatin receptor, was attached to a human antibody backbone. Then a bacteria’s DNA was removed in part and this new gene was spliced into the bacteria DNA’s place. This was all packaged in with a genetic signal to amplify our new frankengene’s expression.
4) What we now have is a vector for our new gene. This bacteria will infect the host with the new DNA and the signal for transcription is amplified in the host organism. Like a Trojan Horse which makes its own Greek soldiers, forever. This will produce the actual antibodies that specifically bind to myostatin. This vector was injected into Chinese hamster ovary cells.
Can’t make this stuff up.
5) The genes are expressed and the antibodies are now free in the hamster cells, the hamster serum is then filtered through a column engineered by GE (makers of washers, dryers, blenders and now hamster ovary cell filters) to grab these antibodies out of the hamster cell serum.
6) These purified antibodies are named ACE-031 and injected into male mice at a concentration of 10mg/kg. That means a adult bodybuilder would have to use 1 gram a month. Gold is $42 a gram. ACE-031 is $150,000 a gram. A gram. Cocaine is $100 per gram. Can you imagine the drug trade for this if it catches on? It is literally almost 4,000 times more valuable than gold.
In this study it was determined that the muscle fiber types I and type II were increased in size (Up to a 22% size increase) but not in number, There was no hyperplasia.
ACE-031 out preformed the control at increasing muscle mass
ACE-031 out preformed the control at increasing muscle mass
This brings up an interesting question: Myostatin null mice (mice genetically engineered to not make myostatin) had mostly if not all type II fiber growth. With the null mice the result was hyperplasia in addition to the hypertrophy. This was not seen with ACE-031. With ACE-031 there were increases in cell size but NOT number, and both cell types, type I and type II.
What makes it even stranger is ACE-031 has a muscle building effect even in null mice. This means even with no potential for an animal to make ANY myostatin, the ACE-031 works to increase muscle.
This clearly points to the possibility that the ACE-031 blocks more than myostatin and some of what it blocks causes hypertrophy and specifically at the type I fibers. This is likely because the myostatin receptor binds more than just myostatin. Myostatin is specific for its receptor but the receptor is not specific for the myostatin. If you recall from the biochemical gene-geneering section above ACE-031 is made from the receptor head and bound to an antibody. But it is clear it doesn’t just target myostatin, it targets things we don’t know about yet….
To See If This Creepy Nanobot Monster Works, Lets Test It on Overweight Women Who Don’t Lift
In one human study 185 lb women were given 250 mg of this a single time. Why on earth overweight women who don’t lift were the test group or why so much was used is beyond me. Humans tend to require a much lower dose pound for pound than mice. 29 days (not 30, 29) later their muscle mass was 1.1 lb higher, in their thighs! With a price tag of over 150$ a mg this means for $37,000 you can have thicker thighs too! If only the tested group had anything to do with the group who would use ACE-031 we would have evidence of a great muscle builder. I can’t believe they performed such a stupid study. Why test obese women who don’t lift?
This is the only completed human trial as of November 2013. Other companies have not surprisingly also began developing this drug but with different names. With a street dose costing about $40,000 it makes sense this may be a huge cash cow and all the pharm companies want in.
Other drugs underdevelopment to block myostatin: LY2495655 (Lilly), Myo-29 (Wyth), ACE-031 (Acceleron/shire), PF-06252616 (Pfizer), BYM-338 (Nova Labs), and about 4 others some are targeting follistatin but the point remains.
BILLIONS of dollars will be spent and made with what could be the next step in muscular evolution the likes of which we haven’t seen since the 60’s when the government developed steroids to give to our olympic athletes so we could beat the USSR.
Nothing in this article or on this site should be considered medical advice or as an endorsement to violate any law of the country in which you reside. The information given is for fun and entertainment purposes only. All claims are 100% dependent upon proper diet and exercise. Please consult a medical practitioner prior to any diet and exercise program.
onlinelibrary.wiley.com/doi/10.1002/mus.23539/abstract
www.ncbi.nlm.nih.gov/pmc/articles/PMC3819341/
jap.physiology.org/content/109/3/621
Cadena SM, Tomkinson KN, Monnell TE, Spaits MS, Kumar R, Underwood KW, Pearsall RS,LacheyJL. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. J Appl Physiol (May 13, 2010). doi: 10.1152/japplphysiol.00866.2009.
Topic Author
:lol: Just legit Follistatin alone would be an expensive addition, nevermind HMP.