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Myostatin (a.k.a. GDF-8) ia a member of the TGF-beta family and is specific to skelet
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| DraftHoodlum_o2 |
Myostatin (a.k.a. GDF-8) ia a member of the TGF-beta family and is specific to skeletal muscles (not found in smooth or cardiac muscles). It is secreted in the inactive (propeptide) form and circulates in the blood. At some point the protein is activated via an as yet unknown mechanism. In vitro studies have pointed to tissue specific (skeletal muscle) metalloproteinases (just an enzyme that cleaves proteins) in the activation but in vivo mechs have not yet been demonstrated. In circulation it has been found to be bound by FLRG and GASP-1; which inhibit its action (Two possible mechs for future control of myostatin activity). Post activation myostatin can then bind to specific receptors on skeletal muscle and activate a signaling cascade which activates factors to regulate transcription of the myostatin target genes. It helps to regulate differentiation, proliferation, and fiber size.
Below are the abstracts from the articles I included
MYOSTATIN REVIEW
Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-â (transforming growth factor-â) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in ‘double muscled’ cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle developmentt. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular rdystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.
MYOSTATIN IN MUSCLE REGENERATION
Purpose of review
Myostatin is an endogenous, negative regulator of muscle growth. Selective inhibition of myostatin may have broad clinical utility by improving regeneration in diverse and burdensome muscle disorders. An understanding of this potential is relevant because inhibitors of myostatin have recently entered clinical trials.
Recent findings: This article reviews the structure and function of myostatin, the effect of inhibiting myostatin in models of disease, and potential therapeutic approaches to blocking myostatin pharmacologically. The possibility that a myostatin inhibitor will promote muscle regeneration in human disease, as seen in animal models, is suggested by the observation that loss of myostatin results in muscle hypertrophy in a human subject.
Summary: Multiple approaches to inhibiting myostatin are suggested by the recent elucidation of its signaling pathway. An inhibitor of myostatin may be the first drug specifically designed to enhance muscle growth and regeneration. |
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| DraftHoodlum_o2 |
also MYOSTATIN AND OTHER DOPING
Advances in recombinant DNA technology have created one of the most powerful weapons in the current doping arsenal: recombinant proteins [Sweeney HL. Gene doping. Sci Am 2004;291:62–9; Unal M, Ozer Unal D. Gene doping in sports. Sports Med 2004;34:357–62]. Recombinant erythropoietin (EPO) and human growth hormone (hGH) are currently being abused but are fortunately detectable either directly by employing isoelectric focusing and immunoassays or indirectly by assessing changes in selected hematopoietic parameters. The detection is technically demanding due to the extent of similarity between the recombinant proteins and their endogenous counterparts.
Another issue facing detection efforts is the speed and conditions at which blood samples are collected and analyzed in a sports setting. Recently, gene doping, which stemmed out of legitimate gene therapy trials, has emerged as the next level of doping. Erythropoietin (EPO), human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), peroxisome proliferator-activated receptor-delta (PPAR ä), and myostatin inhibitor genes have been identified as primary targets for doping. Sports clinical scientists today are racing against the clock because assuring the continued integrity of sports competition depends on their ability to outpace the efforts of dopers by developing new detection strategies.
RESISTANCE LOADING EFFECT ON MYOSTATIN
Myostatin inhibits myoblast proliferation and differentiation in developing muscle. Mounting evidence suggests that myostatin also plays a limiting role in growth/repair/regeneration of differentiated adult muscle by inhibiting satellite cell activation. We tested the hypothesis that myostatin mRNA expression would decrease after resistance loading (RL) with a blunted response in older (O) females (F) who have shown minimal hypertrophy [vs. males (M)] after long-term RL. As myostatin is thought to modulate cell cycle activity, we also studied the response of gene transcripts key to stimulation (cyclin B1 and D1) and inhibition (p21cip and p27kip) of the cell cycle, along with the muscle-specific load-sensitive mitogen mechano-growth factor (MGF). Twenty young (Y; 20-35 yr, 10 YF, 10 YM) and 18 O (60-75 yr, 9 OF, 9 OM) consented to vastus lateralis biopsy before and 24 h after a bout of RL (3 sets x 8-12 repetitions to volitional fatigue of squat, leg press, knee extension). Gene expression levels were determined by relative RT-PCR with 18S as an internal standard and analyzed by age x gender x load repeated-measures ANOVA. A load effect was found for four transcripts (P < 0.005) including myostatin, cyclin D1, p27kip, and MGF as mRNA levels decreased for myostatin (-44%) and p27kip (-16%) and increased for cyclin D1 (34%) and MGF (49%). For myostatin, age x load and gender x load interactions (P < 0.05) were driven by a lack of change in OF, while marked declines were noted in YM (-56%), YF (-48%), and OM (-40%). Higher cyclin D1 levels in OF led to a main age effect (36%, O > Y) and an age x gender interaction (66%, OF > YF vs. 10%, OM > YM; P < 0.05). An age x gender x load interaction (P < 0.05) for cyclin D1 resulted from a 48% increase in OF. Post hoc testing within groups revealed a significant increase in MGF after RL in YM only (91%, P < 0.05). Higher levels of cyclin B1 in O (27%, O > Y) led to a main age effect (P < 0.05). An age x load interaction for cyclin B1 (P < 0.05) was driven by a 26% increase in Y with no change in O after RL. No age or gender differences, or load-mediated changes, were detected in levels of p21cip mRNA expression. These data clearly demonstrate that RL downregulates myostatin expression and alters genes key to cell cycle progression. However, failure to reduce myostatin expression may play a role in limiting RL-induced hypertrophy in OF.
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Disclaimer: I am a medical student and the views I express are by no means to be taken as medical advice; they are my own opinions. Check with your doctor if you want medical advice as he/she has access to more info to give the best advice. Oh yeah, and they have completed med school and residency ;) That being said I am always willing to share my thoughts. |
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| Cosmic Fur |
| I hate to say this, but I was waiting for a "holllaaa bacck" right at the end of it all. |
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| DraftHoodlum_o2 |
| holla backkkkkkkkkkkkkkk |
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| El Kay Dee |
| umm so whats the point of this?:conf: |
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| Cosmic Fur |
| quote: | Originally posted by DraftHoodlum_o2
holla backkkkkkkkkkkkkkk |
Balance is restored in the universe. |
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| DraftHoodlum_o2 |
just sharing some info yo
The subject of myostatin for so many may seem to be a silly notion or simply rubbish, but as I dig deeper into the subject and scour through all the literature I can find I become excited with the possibilities for negatively regulating myostatin. Presently, others that are researching myostatin from a laboratory setting and those associations that cater to people with muscle wasting diseases are also excited from so much promise in the research that has been done thus far.
In the research to determine and identify myostatin inhibitors, the researchers have been investigating for over a year the in vivo regulation of myostatin; in other words, to determine how myostatin is kept in a homeostatic check and balance system within the organism. For a little more information into what myostatin is, without rehashing what that has already been said, myostatin is expressed initially in the myotome compartment of developing somites and continues to be expressed in the myogenic lineage throughout development in adult animals. It is common for one to say that the research is being done with mice and similar animals and that this would not reflect accurately upon the effects in human subjects. Therefore, a consensus would be that research that would yield adequate or desirable results in humans are too far away. That is not necessarily the case with respect to myostatin. Remarkably, the human, rat, murine, porcine, turkey, and chicken myostatin sequences are identical in the biologically active C-terminal portion of the myostatin molecule following the proteolytic processing site. One other factor is to determine the efficacy of animals as a human model in research would be determining a relationship in the function of myostatin between humans and other animals being studied. Fortunately, the function of myostatin appears to be conserved across species, thus improving the efficacy and time frame from animal to human model studies.
A portion of the structure of myostatin has already been mentioned very briefly. Myostatin consists of a disulfide-linked dimer of C-terminal fragments and an N-terminal propeptide in a noncovalently held complex. It is the biologically active C-terminal myostatin dimer that is capable of binding the activin type II (primarily Act RIIB, and, to a lesser extent, Act RIIA). Thus, this binding pattern inhibits muscle growth and especially inhibits hyperplasia. Based upon research it appears that myostatin, like Transforming Growth Factor-beta (TGF-beta) may normally exist in vivo in a latent complex with the propeptide (the portion of the precursor protein upstream of the proteolytic processing site) and that upon activation, myostatin may signal by binding to activin type II receptors. It is the C-terminal dimer that is biologically active in other TGF-beta family members as well.
Thus far, experimentation with the activin-binding protein follistatin and the myostatin propeptide has yielded phenomal results to inhibit the C-terminal dimer’s activity in the regulation of muscle mass.
Most members of the TGF-beta superfamily have been shown to signal by binding serine/threonine kinase receptors followed by activation of Smad proteins. The initial event in triggering the signaling pathway is the binding of the ligand to a type II receptor. During the studies it was observed that the full length of the Act RIIA and Act RIIB receptors bound to myostatin. In vitro the dissociation constant of the myostatin from its cognate receptor is higher than it probably is in vivo. It is very possible that the binding affinity for Act RIIB in vivo is much higher than in vitro since this is known to be the case for other members of the TGF-beta superfamily, especially in the presence of appropriate type I receptors and that other molecules present in vitro are involved in presenting the ligand to the receptor.
By knocking out the Act RIIB kinase domain, researchers were able to transgenically breed a dominant-negative form of Act RIIB in mice. A construct was generated in which a truncated form of Act RIIB lacking the kinase domain was placed downstream of a skeletal muscle-specific myosin light chain promoter/enhancer. By using pronuclear injections, the researchers obtained their founder animals that were dominant-negative Act RIIB for the transgene. These animals showed increases in skeletal muscle mass up to 125% more than the control nontransgenic wild type animals. Evidence suggested that the increased muscle weight resulted from the expression of the transgene without Act RIIB for the binding of the myostatin.
Another construct was made by investigating the effect of the myostatin propeptide. As with the TGF-beta members, it is known that the C-terminal dimer is held in an inactive, latent complex with the other proteins, including their propeptides, and that these propetides can have inhibiting effects on their respective TGF-beta bioactive C-terminal dimer counterparts. Indeed this is true with myostatin, yet 50 times as much propeptide is required (roughly 23.5 nM) compared to the approximate 470 pM of follistatin to obtain the inhibitory effects on the myostatin molecule.
As mentioned, follistatin was part of this research as well. Since follistatin was part of the study, follistatin yielded the most phenomenal results. Follistatin has been known to be capable of binding and inhibiting the activity of several TGF-beta family members, and, of interest, follistatin can block the activity of GDF-11, which is highly related to myostatin. From the research conducted with follistatin, it appears that follistatin is a normal in vivo regulator preventing overactivity of myostatin as part of the body’s checks and balances system for homeostasis. The muscle weights in the follistatin constructs were increased by 194% - 327% relative to the control animals. There was a 66% increase in muscle fibers (hyperplasia) and a 28% increase in fiber diameter (hypertrophy).
Concerning the truncated form of the Act RIIB as previously discussed, one possibility that makes excess muscle growth occur may not be that the truncated receptor is blocking the signaling in the target cell but is acting as a sink to deplete extracellular concentrations of myostatin. One other possibility is that the truncated receptor is blocking signaling of other ligands besides myostatin. To my knowledge as of yet, it is not known definitively that follistatin is blocking myostatin activity in vivo to promote muscle growth. With the extraordinary degree of muscling in one of the founder animals compared to the rest of the follistatin construct founders, it is probable that other follistatin sensitive ligands may be involved in regulating muscle growth. One obvious candidate would be GDF-11, which is so closely related to myostatin, and GDF-11 is also expressed in skeletal muscle tissue. Other candidate ligands would include the activins, which has been shown to be capable of inhibiting muscle cell differentiation in vitro.
Thus far, the data that has been uncovered suggest that myostatin antagonists, such as follistatin and the myostatin propeptide, or activin type II receptor antagonists may be highly effective muscle enhancing agents for human applications. Of course, additional experiments will be required and are being done successfully at present to unfold a deeper understanding of blocking myostatin’s inhibitory effects on muscle growth and identification of other signaling components as well as designer-antibody antagonists. |
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| DraftHoodlum_o2 |
| all i know is i have been cycling this product now for 2 months and my balls are hurting what should i do ? |
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| Floorwhore |
| quote: | Originally posted by DraftHoodlum_o2
all i know is i have been cycling this product now for 2 months and my balls are hurting what should i do ? |
1.) make small incision in ball sac
2.) pinch ball sac until testes fall to ground
3.) blow dog whistle, watch sparky eat what appears to be meatballs from chef boyardee, and likely puke them up and die from the poison that had invaded your scrotal region.
4.) buy new dog. |
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| DraftHoodlum_o2 |
| quote: | Originally posted by Floorwhore
1.) make small incision in ball sac
2.) pinch ball sac until testes fall to ground
3.) blow dog whistle, watch sparky eat what appears to be meatballs from chef boyardee, and likely puke them up and die from the poison that had invaded your scrotal region.
4.) buy new dog. |
thanks dawgy after that i can go buy some tribulis supplements to rebuild and increase sperm count,potencey |
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| VERTiG0 |
For extra fun for the ladies, get some L-Arginine an L-Lysine too! They'll love you for it!*
*probably not |
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| rabbitjoker |
| EAS Myoplex meal replacement is what he's talking about (or MetRX). |
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