Instead of muddying the waters of the hypertrophy thread I though I would post this here for discussion. This is a interesting relationship. Its not new news as identification goes of this relationship goes back several years. Still this study has some tidbits taht had not been previously identified.

So what do you think is modulation of follistatin a viable target for myostatin inhibition.

I'd certainly give it a go if 1) I knew how to dose it properly; and 2) it weren't so expensive:

http://www.researchd.com/cytokines/rdi1213.htm

Role of myostatin in metabolism.
Current Opinion in Clinical Nutrition & Metabolic Care. 7(4):451-457, July 2004.
Gonzalez-Cadavid, Nestor F; Bhasin, Shalender
Abstract:
Purpose of review: To review papers on myostatin published in 2003 and early 2004. Myostatin is a negative regulator of skeletal muscle mass produced in this tissue. Inactivating mutations of the myostatin gene or interaction of myostatin protein with follistatin and other inhibitory proteins induce a hypermuscular phenotype in cattle and mice; this is assumed to result from inhibition of muscle cell proliferation and DNA and protein synthesis (antianabolic effects). Myostatin also controls muscle mass in other animals, and appears to affect adipose tissue mass.

Recent findings: New protein interactions inhibiting myostatin that lead to double muscling, as well as the induction of hypermuscularity with myostatin antibodies, or the generation of a myostatin conditional knockout mouse, have been reported. Conversely, a transgenic mouse over-expressing myostatin and exhibiting reduced muscle mass in a gender-specific process has been obtained. In addition, novel inactivating mutations in the myostatin gene and genetic loci regulating myostatin effects, and the characterization of the myostatin gene and its effects on metabolism in fish and chicken have been described. Finally, the regulation of myostatin levels by growth hormone, glucorticoids, anabolic agents, nutritional status and exercise, the characterization of myostatin signaling pathways, and the clarification of myostatin effects on cell replication and differentiation, are other important recent findings.

Summary: These studies suggest that proteins and drugs that inactivate myostatin, or interfere with its binding to its receptor, may be useful for the therapy of wasting and degenerative muscle diseases and for the food industry. Other promising approaches may derive from new insights into the biochemical cascade that mediates myostatin effects, and into the role of myostatin in the regulation of fat metabolism and of heart and muscle regeneration after injury.

© 2004 Lippincott Williams & Wilkins, Inc.


I don't have the full text, but once they elucidate the type of drugs that interfere with Myostatin binding, that gives us a direction to look supplement-wise. Another study also involved Activin, as a competitive inhibitor of Follistatin. Maybe another target there?

My concern would be with the many other roles of follistatin in the body. Sure it might deactivate myostatin but it also downregulates the action of lots of other things, like GnRH. I could be wrong, maybe pituitary follistatin is different than the kind we are talking...but check this out...



Maybe a way to specifically target skeletal muscle production of follistatin? The ultimate post workout sup heh?

Yes...we actually looked at HDAC inhibitors a while back. I have already found something that qualifies as both a supplement and a potent HDAC inhibitor.

We are still researching it.

oh well, i tried...

No, it's not that at all. I know I have not been able to dedicate the necessary time and effort, due to the new product launches, etc. It's just unknown at this time what effect, if any, it would have on muscle hypertrophy.

I'm sure it's only a matter of time before the "research chemical" distributors get their hands on the anti-myostatin antibodies that Wyeth is working on. I'd go long Wyeth if it weren't for the prospect of the multibillion dollar Premarin lawsuits hanging over their head.

When they first started pimping the myostatin inhibitors, follistatin was the only thing I could find in my research that seemed like a possible candidate for being their uber-secret wonder ingredient. Didn't find anything suggesting oral bioavailability, so i did not go beyond that.

As far as HDAC, it is involved in all kinds of signal transduction pathways, so it is not like it is something that I consider a clean and pretty, miracle target at this point, just something really interesting for future research. But, as matt said, there is a supplement that should be pretty easy to source and produce that has been found to inhibit it in numerous studies (used specifically for this purpose in the literature)

I would agree...especially since certain HDAC inhibitors have been shown to increase GLUT4 concentration PREFERENTIALLY in skeletal muscle...add in the benefit of muscle specific follistatin expression....

Its also quite interesting that HDAC's inhibit preadipocyte differentiation. Though they do not prevent mitotic clonal expansion. So it would seem that it might be an attractive target.

Very interesting.

The stuff I found is cheap, so I might have them send some samples and do some "self-experimentation".

Its not at all clear what would happen in vivo though. As this study shows.



So what will happen in the human body is anyones guess.

The more I think about this the more it sounds like HDAC's work through SIRT1 in mamalian adipose tissue to prevent adipogenesis.

SIRT1 PROFOUNDLY controls adipogensis in vivo and in my opinion is largely responsible for the mobilization of fatty acids during caloric restriction as it is dramatically upregulated by caloric restriction and is our bodys natural PPAR-gamma antagonist. It binds the PPAR cofactor and prevents PPAR-gamma transcription from taking place.

I still have not quite figured this out yet though. At least not to the point where I feel comfortable. Anyway sorry for detailing the thread on adipose issue but I though you guys might find this interesting.

Sodium Butyrate is a potent HDAC inhibitor and is already available in supplement form and used for lower bowel conditions. Not shure if this is what Avant's team is referring to? Could this possibly be used to do the things that we are speculating on?

I haven't has a chance to read Nandi's article on androgens and stem cells in full, but at what point in the pathway does the barnching occur?? Another one of the things that HDAC does is dephosphoylate the androgen receptor. IOW, an inhibitor should increase androgen signalling.

The authors are unfortunately somewhat vague in their description of the exact point where branching occurs. According to their research, androgens prevent branching of mesenchymal stem cells into "preadipocyte progenitor cells". The latter are of adipogenic lineage, evidently one step removed from differentiation into true preadipocytes. The authors failed to describe what distinguishes these progenitor cells (in terms of gene expression) from the stem cells and the more highly differentiated preadipocytes. Clearly it is the expression of one or more genes not expressed in the stem cells, and a lack of gene expression found in true preadipocytes. I was unable to find any literature that shed more light on this. I emailed the senior author regarding this but thus far have not received a response.

Jsut some evidence supporting Sirt1's conttribution.





see also

http://www.pubmedcentral.nih.gov/articlere...ubmedid=9405624

Hmm...so would PPAR-Gamma antagonists extend lifespan without the need for caloric restriction (fasting), or is it the interaction with the cofactors that extend?

well personally I think caloric restriction increases life span by slowing metabolism and decreasing inflamatory cytokine production. But honestly my theory is as good as anyone elses in this matter. No one knows for sure.

That's mine as well.

Although it doesn't answer the question Par posed about exactly where adipocyte/myocyte branching occurs under the influence of androgens, or actually even have anything to do with it, I thought some readers might enjoy this review of the sequence of gene activation in preadipocytes on their way to becoming fat cells.

http://www.nutrition.org/cgi/content/full/130/12/3122S

hello new here. just wondering if anyone knows about either myo-029 or myo-29(seen it printed both ways). tested by wyeth phamaceuticals on human subjects, started sometime in summer of 04.

howdy there. First off: Bump.

second: what textbooks would one have to familiarize oneself with to cut through all this biochemical mumbo-jumbo and see what you kids are chattering on about?
(I'm assuming a general Genetics textbook and a Biochem book, but maybe somone could be a bit more specific)


Thanks!

Ds - anything that you can bring us up to speed on the last 3.75 years since?



Was Miles refering to your subsance brought up here?

Also, have we determined if Spook was correct about SIRT-1 inolvement? If so what kind of negative feedback coudl we expect?

If SB really was the ingredient does anyone have any experiences they'd like to share?

I'll be reviving my anabolism thread and first order of business is to tie up old loose ends that I skipped over because my tiny brain was over whelmed.

What?

yes yes crowned.... Bumpasaurus Rex bitches.

What about Tributyrin? It's a liquid but it can be capped. It burns slightly to swallow on its own but it has no discernible smell or flavour.


I capped it by taking a block of wood, drilling holes into it (not through it) to support the capsules. Fill the capsules and press the top on tightly. As long as the capsule remains upright, it won't leak.

I'm taking 6 capsules 3 times per day. Each capsule is 00 in size and holds slightly more than 0.5ml. This works out to about 9 grams per day I believe.

I just started. It seems to be well tolerated.

... ok I get that Tributyrin is a lipolytic enzyme, but what effect are you going after with it's oral consumption? Data? Relevance? Not trying to abrasive. I guess I'm requesting an explination of the why instead of the how.

Synonym: glyceryl tributyrate, tributyrylglycerol.

Tributyrin, a Stable and Rapidly Absorbed Product of Butyric Acid.......like sodium butyrate only 3 time more potent per mole. Butyrate is an HDAC inhibitor which has been shown to increase follistatin in a similar manner to Trichostatin A.


http://jn.nutrition.org/cgi/content/full/131/6/1839
..."In spite of its early promise, butyrate is not among the drugs used for cancer treatment. The major problem has been to achieve and maintain its millimolar concentrations in blood. Butyrate is metabolized rapidly as soon as it enters the colonocyte via its active transport system (11Citation 12Citation 13Citation) , and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions. A prodrug of natural butyrate, tributyrin, is a neutral short-chain fatty acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a drug (14)Citation . Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. Compared with butyrate, tributyrin has more favorable pharmacokinetics (14Citation 15Citation 16Citation) and is well tolerated (17)Citation . Liquid tributyrin filled into gelatin capsules and administered orally resulted in millimolar concentrations of butyrate both in plasma and inside the cell (17)Citation . In vitro, tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells (18Citation 19Citation 20)Citation . In this study, human colon cancer cells (Caco-2) were used to investigate the effects of tributyrin on growth and differentiation."

Any evidence regarding its efficacy for raising follistatin? Anything comparing it to trichostatin A? I've read of numerous people taking rather substantial doses for prolonged periods with side effects noted such as "anorexia, weight loss etc.". It didn't appear to stimulate muscle specific follistatin to any appreciable extent...well, not to any extent we would appreciate.

http://www.sciencedirect.com/science?_ob=A...ec6bf3836c13856


Deacetylase Inhibitors Increase Muscle Cell Size by Promoting Myoblast Recruitment and Fusion through Induction of Follistatin

Simona Iezzi1, 5, Monica Di Padova1, 5, Carlo Serra2, 5, Giuseppina Caretti1, Cristiano Simone2, 3, Eric Maklan1, Giulia Minetti2, Po Zhao4, Eric P. Hoffman4, Pier Lorenzo Puri2, 3 and Vittorio SartorelliCorresponding Author Contact Information, 1, Corresponding Author Contact Information, E-mail The Corresponding Author

1 Muscle Gene Expression Group, Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA

2 Laboratory of Gene Expression, Dulbecco Telethon Institute, Fondazione A. Cesalpino Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome 00128, Italy

3 The Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92093, USA

4 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA

Received 10 September 2003;
Revised 5 February 2004;
accepted 17 March 2004
Published: May 10, 2004
Available online 11 May 2004.

Tributyrin isn't mentioned, neither is it expressed the extent to which HDAC inhibitors' cell-specific follistatin upregulation will induce skeletal muscle hypertrophy/hyperplasia via oral bolus.
In other words, how much tributyrin does it take to get the far right mouse:

Tributryin as mentioned is butyric acid prodrug. Butyrate is mentioned in that article and others as having an affect on follistatin.

As for how much butryate or in my case Trybutrin, is needed, I don't know. Someone has to try, so I thought I would. So far there seems to be some visible recomposition. It's too early to say one way or the other.


Butyrate is a very weak HDACi and pretty non specific. However it is cheap, readily available, well tolerated, with no notable side effects.

Rock on, intrepid one.