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  1. #1
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    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.



    Dev Biol. 2004 Jun 1;270(1):19-30.* Related Articles, Links*



    *

    Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis.



    Amthor H, Nicholas G, McKinnell I, Kemp CF, Sharma M, Kambadur R, Patel K.



    Department of Veterinary Basic Sciences, Royal Veterinary College, London NW1 OTU, UK.



    Follistatin is known to antagonise the function of several members of the TGF-beta family of secreted signalling factors, including Myostatin, the most powerful inhibitor of muscle growth characterised to date. In this study, we compare the expression of Myostatin and Follistatin during chick development and show that they are expressed in the vicinity or in overlapping domains to suggest possible interaction during muscle development. We performed yeast and mammalian two-hybrid studies and show that Myostatin and Follistatin interact directly. We further show that single modules of the Follistatin protein cannot associate with Myostatin suggesting that the entire protein is required for the interaction. We analysed the interaction kinetics of the two proteins and found that Follistatin binds Myostatin with a high affinity of 5.84 x 10(-10) M. We next tested whether Follistatin suppresses Myostatin activity during muscle development. We confirmed our previous observation that treatment of chick limb buds with Myostatin results in a severe decrease in the expression of two key myogenic regulatory genes Pax-3 and MyoD. However, in the presence of Follistatin, the Myostatin-mediated inhibition of Pax-3 and MyoD expression is blocked. We additionally show that Myostatin inhibits terminal differentiation of muscle cells in high-density cell cultures of limb mesenchyme (micromass) and that Follistatin rescues muscle differentiation in a concentration-dependent manner. In summary, our data suggest that Follistatin antagonises Myostatin by direct protein interaction, which prevents Myostatin from executing its inhibitory effect on muscle development.



    PMID: 15136138 [PubMed - indexed for MEDLINE]
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    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
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    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?
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    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...



    Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin.



    Iezzi S, Di Padova M, Serra C, Caretti G, Simone C, Maklan E, Minetti G, Zhao P, Hoffman EP, Puri PL, Sartorelli V.



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



    Fusion of undifferentiated myoblasts into multinucleated myotubes is a prerequisite for developmental myogenesis and postnatal muscle growth. We report that deacetylase inhibitors favor the recruitment and fusion of myoblasts into preformed myotubes. Muscle-restricted expression of follistatin is induced by deacetylase inhibitors and mediates myoblast recruitment and fusion into myotubes through a pathway distinct from those utilized by either IGF-1 or IL-4. Blockade of follistatin expression by RNAi-mediated knockdown, functional inactivation with either neutralizing antibodies or the antagonist protein myostatin, render myoblasts refractory to HDAC inhibitors. Muscles from animals treated with the HDAC inhibitor trichostatin A display increased production of follistatin and enhanced expression of markers of regeneration following muscle injury. These data identify follistatin as a central mediator of the fusigenic effects exerted by deacetylase inhibitors on skeletal muscles and establish a rationale for their use to manipulate skeletal myogenesis and promote muscle regeneration.


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

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    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.
    Genomyx....Evolution in Action.

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    Quote Originally Posted by D Sade' date='Jul 5 2004, 01:07 PM
    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...

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    Quote Originally Posted by BigSkeptic' date='Jul 5 2004, 02:30 PM
    [quote name='D Sade' date='Jul 5 2004, 01:07 PM'] 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... [/quote]

    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.
    Genomyx....Evolution in Action.

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  8. #8
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    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.
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    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)


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    Quote Originally Posted by Par Deus' date='Jul 7 2004, 07:46 AM
    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....

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    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.
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    Quote Originally Posted by Spook' date='Jul 12 2004, 05:33 AM
    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".
    Genomyx....Evolution in Action.

    "Blood, Sweat, and Tears doesn't mean crying while you struggle to put your tampon in." ~D Sade

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    Lesson # 4 - There is no such thing as a safe environment.
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    Paltry death cannot hold me for long.
    Can it be that I am stronger, even, than...me?" ~D Sade, written to Bizarro D Sade
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  13. #13
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    J Biol Chem. 2004 Apr 30;279(18):18851-60. Epub 2004 Feb 24. Related Articles, Links*



    *

    Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis.



    Lagace DC, Nachtigal MW.



    Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.



    Adipogenesis is dependent on the sequential activation of transcription factors including the CCAAT/enhancer-binding proteins (C/EBP), peroxisome proliferator-activated receptor gamma (PPARgamma), and steroid regulatory element-binding protein (SREBP). We show that the mood stabilizing drug valproic acid (VPA; 0.5-2 mm) inhibits mouse 3T3 L1 and human preadipocyte differentiation, likely through its histone deacetylase (HDAC) inhibitory properties. The HDAC inhibitor trichostatin A (TSA) also inhibited adipogenesis, whereas the VPA analog valpromide, which does not possess HDAC inhibitory effects, did not prevent adipogenesis. Acute or chronic VPA treatment inhibited differentiation yet did not affect mitotic clonal expansion. VPA (1 mm) inhibited PPARgamma induced differentiation but does not activate a PPARgamma reporter gene, suggesting that it is not a PPARgamma ligand. VPA or TSA treatment reduced mRNA and protein levels of PPARgamma and SREBP1a. TSA reduced C/EBPalpha mRNA and protein levels, whereas VPA only produced a decrease in C/EBPalpha protein expression. Overall our results highlight a role for HDAC activity in adipogenesis that can be blocked by treatment with VPA.



    PMID: 14985358 [PubMed - indexed for MEDLINE]


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



    Dev Cell. 2002 Dec;3(6):903-10.* Related Articles, Links*



    *

    The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation.



    Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J.



    Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.



    The retinoblastoma protein (RB) has previously been shown to facilitate adipocyte differentiation by inducing cell cycle arrest and enhancing the transactivation by the adipogenic CCAAT/enhancer binding proteins (C/EBP). We show here that the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor pivotal for adipogenesis, promotes adipocyte differentiation more efficiently in the absence of RB. PPARgamma and RB were shown to coimmunoprecipitate, and this PPARgamma-RB complex also contains the histone deacetylase HDAC3, thereby attenuating PPARgamma's capacity to drive gene expression and adipocyte differentiation. Dissociation of the PPARgamma-RB-HDAC3 complex by RB phosphorylation or by inhibition of HDAC activity stimulates adipocyte differentiation. These observations underscore an important function of both RB and HDAC3 in fine-tuning PPARgamma activity and adipocyte differentiation.



    PMID: 12479814 [PubMed - indexed for MEDLINE]


    So what will happen in the human body is anyones guess.
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  14. #14
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    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.



    Cell Mol Life Sci. 2003 Sep;60(9):1990-7.* Related Articles, Links*





    Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases.



    Kyrylenko S, Kyrylenko O, Suuronen T, Salminen A.



    Department of Neuroscience and Neurology, University of Kuopio, 70211 Kuopio, Finland.



    The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and histone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mRNAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 were downregulated by trichostatin A (TSA) and n-butyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the upregulation of SIRT2 expression with TSA is related to the hyperacetylation of DNA-bound histone H4 within the first 500 bp upstream of the transcription start site of the SIRT2 gene. Chemically different types of HDAC inhibitors, such as TSA, apicidin, SAHA, M344 and n-butyrate induced remarkably similar responses in SIRT1-7 mRNA expression patterns. Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status.



    PMID: 14523559 [PubMed - indexed for MEDLINE]
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    Quote Originally Posted by D Sade' date='Jul 12 2004, 08:02 AM
    [quote name='Spook' date='Jul 12 2004, 05:33 AM'] 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". [/quote]

    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?

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    Senior Member Par Deus's Avatar
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    Quote Originally Posted by Spook' date='Jul 12 2004, 04:33 AM
    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.


    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.


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    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.
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    Jsut some evidence supporting Sirt1's conttribution.



    Nature. 2004 Jun 17;429(6993):771-6. Epub 2004 Jun 02. Related Articles, Links*



    *

    Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.



    Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Oliveira RM, Leid M, McBurney MW, Guarente L.



    Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.



    Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage. Sirt1 represses PPAR-gamma by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). Mobilization of fatty acids from white adipocytes upon fasting is compromised in Sirt1+/- mice. Repression of PPAR-gamma by Sirt1 is also evident in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuates adipogenesis, and RNA interference of Sirt1 enhances it. In differentiated fat cells, upregulation of Sirt1 triggers lipolysis and loss of fat. As a reduction in fat is sufficient to extend murine lifespan, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.



    PMID: 15175761 [PubMed - in process]


    Cell. 2004 Feb 20;116(4):511-26.* Related Articles, Links*



    *

    A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.



    Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG.



    Howard Hughes Medical Institute, Department of Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla 92093, USA.



    The mechanisms that control the precisely regulated switch from gene repression to gene activation represent a central question in mammalian development. Here, we report that transcriptional activation mediated by liganded nuclear receptors unexpectedly requires the actions of two highly related F box/WD-40-containing factors, TBL1 and TBLR1, initially identified as components of an N-CoR corepressor complex. TBL1/TBLR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex, with TBLR1 selectively serving to mediate a required exchange of the nuclear receptor corepressors, N-CoR and SMRT, for coactivators upon ligand binding. Tbl1 gene deletion in embryonic stem cells severely impairs PPARgamma-induced adipogenic differentiation, indicating that TBL1 function is also biologically indispensable for specific nuclear receptor-mediated gene activation events. The role of TBLR1 and TBL1 in cofactor exchange appears to also operate for c-Jun and NFkappaB and is therefore likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.



    PMID: 14980219 [PubMed - indexed for MEDLINE]


    see also



    http://www.pubmedcentral.nih.gov/articlere...ubmedid=9405624
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    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?
    Genomyx....Evolution in Action.

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    Paltry death cannot hold me for long.
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    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.
    Normal Person + Anonymity + Audience = Total Fuckwad.
    If you meet the bodybuilding guru on the information super-highway, kill the bodybuilding guru.
    trust != truth

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