Another myostatin inhibitor explained.

[Dr Pangloss]

This works by making the normally cell-surface receptor for myostatin into a truncated form that is "soluble' and just floats around, not connected to the signal-transduction system. it binds myostatin and thereby inhibits myostatin from binding the cell-surface receptor and inhibiting muscle formation.

here is a schematic of roughly how it's made:

Alk7.jpg

[Dr Pangloss]

1: Exp Neurol. 2009 Mar 11. [Epub ahead of print] Links

A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis.

Morrison BM, Lachey JL, Warsing LC, Ting BL, Pullen AE, Underwood KW, Kumar R, Sako D, Grinberg A, Wong V, Calantuoni E, Seehra JS, Wagner KR.
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.

[Strikerrjones]

Does myostatin do anything beneficial?

[Dr Pangloss]

Does myostatin do anything beneficial?

It keeps people from retaining too much muscle.

[SilverBAK]

It would be interesting if we could list all the currently available and still being researched myostatin inhibitors so that we could educate ourselves on each one and how they are different

[SilverBAK]

http://jap.physiology.org/cgi/content/full/102/6/2142

"The present study is one of the first to explore haplotype structure of candidate genes and their associations with skeletal muscle phenotypes and shows for the first time that the ACVR2B and follistatin loci may contribute to interindividual variation in muscle mass and strength. The results show that follistatin haplotype 3 is associated with lower skeletal muscle mass in men and that ACVR2B Hap Group 1 is associated with lower skeletal muscle strength in women. Although these associations cannot be verified as causal from the present data, the use of haplotype structure in the present study accounts for a greater fraction of genetic variation than single-polymorphism studies. The results of the present study can be used to generate specific hypotheses regarding the genetic influence of the target genes on muscle phenotypes, and subsequent studies can be aimed at identifying the causal variant(s) associated with each haplotype as well as its mechanism of action (31). The strong role of myostatin in both muscle development and the maintenance of muscle mass in adults (22) provides a rationale to address whether genetic variation in members of its pathway (e.g., ACVR2B and follistatin) influence muscle phenotypes. The molecular basis for the haplotype associations observed for the ACVR2B and follistatin genes with skeletal muscle phenotypes is uncertain and cannot be addressed by the present study; however, we speculate that these associations may be the result of altered ACVR2B (myostatin receptor) activity, either directly through genetic influence on ACVR2B itself or indirectly through the influence of follistatin. Follistatin has been shown to have a strong affinity for myostatin and can completely prevent myostatin receptor activation and downstream phosphorylation of Smad3 (1). Phosphorylation of Smad3, a key step in the myostatin cascade in negatively regulating skeletal muscle, induces binding of Smad3 to MyoD and represses the activity of the MyoD family of transcription factors, resulting in inhibition of myoblast differentiation (16, 19). On the basis of these relationships, it can be hypothesized that a causal mutation, yet to be identified within the target genes, leads to either increased activity of myostatin (via lower follistatin inhibition) or greater ACVR2B activation, which would result in greater phosphorylation of Smad3. Such influences could be envisioned to affect either total muscle mass or fiber-type composition, the latter of which would have relevance to muscle strength or muscle quality. The soleus muscle of myostatin null mice displays a larger proportion of fast-twitch type II fibers and a reduced proportion of slow-twitch type I fibers compared with wild-type animals (9). Thus higher receptor activation (e.g., due to genetic variation in follistatin haplotype 3, or ACVR2B Hap Group 1) would be envisioned to result in lower muscle mass and/or lower type II fiber proportions. Obviously, further studies will be required to test these hypotheses, but the present results do provide support for the generation of such hypotheses."

I wonder if any guys are experimenting with exogenous follistatin administration?

[Dr Pangloss]

Follistatin and follistatin related protein bind to and inhibit myostatin, but there is no direct evidence that follistatin or FRP work to enhance muscle mass. Follistatin and FRP also bind activin and prehaps other members of the tgf-beta superfamily (activin and myostatin belong to this large family). follistatin knockout animals don't get big muscles...

myostatin proprotein, an immature form of myostatin, apparently enhances muscle mass in animal models.

myo-29, a monoclonal antibody to mysotatin, works in animal models and has a more modest effect in human trials.

Fragments of ActivinIIB receptor that are free floating and soluble (ie, the above) also work.

[SilverBAK]

follistatin and follistatin related protein bind to and inhibit myostatin, but there is no direct evidence that follistatin or frp work to enhance muscle mass. Follistatin and frp also bind activin and prehaps other members of the tgf-beta superfamily (activin and myostatin belong to this large family). Follistatin knockout animals don't get big muscles...

myostatin proprotein, an immature form of myostatin, apparently enhances muscle mass in animal models.

myo-29, a monoclonal antibody to mysotatin, works in animal models and has a more modest effect in human trials.

fragments of activiniib receptor that are free floating and soluble (ie, the above) also work.

acvr2b?

[Dr Pangloss]

acvr2b?

that's activin receptor BII. IT's actually fragments of it, which i have included above. using the whole thing doesn't work. It's a membrane protein.

[Luka Treska]

That's pretty cool, but I'm guessing this would act in a competitive manner with the body's own receptors? If so, then would one be able to get the same result with every injection? And also does it work locally or systemically (I'm guessing the latter)?

[Dr Pangloss]

That's pretty cool, but I'm guessing this would act in a competitive manner with the body's own receptors? If so, then would one be able to get the same result with every injection? And also does it work locally or systemically (I'm guessing the latter)?

In the paper its systemic injection. Since it antagonizes by simply binding myostatin it should be dose-dependent, so you should be able to get similar results with repeated administratin.

This is the kind of thing that could be made in a lab easily, but i would not expect anyone to jump in and make it available underground until clinicals have been (at least stage II) concluded successfully.

[Luka Treska]

Thank you for the clerification. In your honest opinion (I don't know much about myostatin inhibitors) could this compound be comparable to AAS (or the usual pro drug protocols today) as far as muscle gains go...could it be even better?

I know this PLUS all the goods already available will be much better, but a lot of people say once myostatin inhibitors are in production, AAS will become a thing of the past (I doubt it, but as I said, I don't know much about myostatin inhibitors).

[Dr Pangloss]

Thank you for the clerification. In your honest opinion (I don't know much about myostatin inhibitors) could this compound be comparable to AAS (or the usual pro drug protocols today) as far as muscle gains go...could it be even better?

I know this PLUS all the goods already available will be much better, but a lot of people say once myostatin inhibitors are in production, AAS will become a thing of the past (I doubt it, but as I said, I don't know much about myostatin inhibitors).

Judging by the results of total mysostatin inhibition (ie, the myo knockout dog and cow), strong myostatin inhibitors will be better than anything so far. Dogs and Cows have been admininistered steroids and growth hormone for various reasons for years but nothing ever looked like the myo knockout dogs or bulls.

If the other stuff is additive and not occlusive (you know, they work independently so you get gains from both), myostatin inhibitors will not render the other drugs obsolete.

[Luka Treska]

Judging by the results of total mysostatin inhibition (ie, the myo knockout dog and cow), strong myostatin inhibitors will be better than anything so far. Dogs and Cows have been admininistered steroids and growth hormone for various reasons for years but nothing ever looked like the myo knockout dogs or bulls.

If the other stuff is additive and not occlusive (you know, they work independently so you get gains from both), myostatin inhibitors will not render the other drugs obsolete.

That's a good point, I never saw it that way. Geez if the human results look anything like the dog and cows plus all the gear bodybuilders already take, it will be something I can't even imagine at this point.

[Yolo]

Myostating inhibition is, indeed, a fascinating prospect. I am curious about the side-effects myostatin inhibition might have on the heart though...