Creatine, HMB and Leucine Suppress Myostatin (In Vitro)

CFC

CFC

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We already know that Clenbuterol (at high doses) and especially Creatine are decent myostatin blockers; this study was interesting in theorising a possible synergistic effect between Creatine, HMB and Leucine in reducing the effect of myostatin in vitro.


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J Int Soc Sports Nutr. 2014 Aug 13;11:38.
L-leucine, beta-hydroxy-beta-methylbutyric acid (HMB) and creatine monohydrate prevent myostatin-induced Akirin-1/Mighty mRNA down-regulation and myotube atrophy.
BACKGROUND:

The purpose of this study was to examine if L-leucine (Leu), β-hydroxy-β-methylbutyrate (HMB), or creatine monohydrate (Crea) prevented potential atrophic effects of myostatin (MSTN) on differentiated C2C12 myotubes.

METHODS:

After four days of differentiation, myotubes were treated with MSTN (10 ng/ml) for two additional days and four treatment groups were studied: 1) 3x per day 10 mM Leu, 2) 3x per day 10 mM HMB, 3) 3x per day 10 mM Crea, 4) DM only. Myotubes treated with DM without MSTN were analyzed as the control condition (DM/CTL). Following treatment, cells were analyzed for total protein, DNA content, RNA content, muscle protein synthesis (MPS, SUnSET method), and fiber diameter. Separate batch treatments were analyzed for mRNA expression patterns of myostatin-related genes (Akirin-1/Mighty, Notch-1, Ski, MyoD) as well as atrogenes (MuRF-1, and MAFbx/Atrogin-1).

RESULTS:

MSTN decreased fiber diameter approximately 30% compared to DM/CTL myotubes (p < 0.001). Leu, HMB and Crea prevented MSTN-induced atrophy. MSTN did not decrease MPS levels compared to DM/CTL myotubes, but MSTN treatment decreased the mRNA expression of Akirin-1/Mighty by 27% (p < 0.001) and MyoD by 26% (p < 0.01) compared to DM/CTL myotubes. shRNA experiments confirmed that Mighty mRNA knockdown reduced myotube size, linking MSTN treatment to atrophy independent of MPS. Remarkably, MSTN + Leu and MSTN + HMB myotubes had similar Akirin-1/Mighty and MyoD mRNA levels compared to DM/CTL myotubes. Furthermore, MSTN + Crea myotubes exhibited a 36% (p < 0.05) and 86% (p < 0.001) increase in Akirin-1/Mighty mRNA compared to DM/CTL and MSTN-only treated myotubes, respectively.

CONCLUSIONS:

We demonstrate that leucine, HMB, and creatine monohydrate reverse myostatin-induced atrophy in myotubes; this potentially results from the independent action of each ingredient modulating Akirin-1/Mighty mRNA expression. Furthermore, our findings suggest that, in spite of MSTN treatments, creatine monohydrate treatment up-regulates Akirin-1/Mighty mRNA which leads to a hypertrophic effect clearly independent of muscle protein synthesis. Future in vivo studies should continue to examine how leucine, HMB, and/or creatine monohydrate independently or synergistically affect Akirin-1/Mighty gene expression. More importantly, while Akirin-1/Mighty gene expression is needed for the maintenance of myofiber size as reported herein, further research is needed in order to examine how Akirin-1/Mighty gene expression mechanistically relates to skeletal muscle hypertrophy in vivo.

http://www.ncbi.nlm.nih.gov/pubmed/25132809
 
This is an extremely interesting summary. Majority of studies/supplements in regards to myostatin manipulation are generally bogus, but this is the first one I've seen in regards to experimental gene therapy in that department. I took genetics for a semester, but its still pretty difficult to comprehend the whole study. It is stating that it successfully inhibited myostatin's effects on muscle protein synthesis, however I don't see anything about the duration that may be required to continually exacerbate the effect. Usually gene therapy isn't just a one vector deal, correct? It requires multitude of attempts and I remember the complexity of successfully integrating the genetically engineered DNA into the subject's genome and avoiding an immune response or possibly altering a sensitive coding sequence leading to unwanted mutagenesis.

EDIT: I misunderstood this study. So it successfully inhibited myostatin's influence at the genetic level, yet no substance was introduced via a vector? If this was done in vivo, wouldn't the expressions be corrected due to the body's natural maintenance of genomic integrity and the inevitable cell cycle and its DNA checkpoints? Or would the alteration to the expression not be recognized as a heritable mutation and it could then replicate itself?
 
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I think you're getting a bit mixed-up with gene therapy here GrymReefer. Gene therapy is where you attempt to insert a gene into a patient's cell: this is not gene therapy. This is simply administering various compounds (in this instance Creatine, HMB and Leucine) and seeing what effect they have on myostatin expression and function. Many compounds are known to affect the expression or function of myostatin (I mentioned Clen above which is particularly well-known). The benefit of these three is that they are readily available and (unlike clen) without deleterious health effects. You can read the entire study through the link as its an open-access paper.
 
Ya I reread it after coming to a more sober state of mind and realized I completely missed the big picture and made a fool of myself. Made the equation more complicated than it originally was.
 
GrymReefer said:
Ya I reread it after coming to a more sober state of mind and realized I completely missed the big picture and made a fool of myself. Made the equation more complicated than it originally was.
Click to expand...

We've all been there, don't worry about it.. Your contribution here is most welcome, please continue... A healthy intellectual debate is what we like to promote here in SD..
 
So enlighten me on this if I'm still somehow missing the ballpark.... The synergenic effects created from the combination of the substances allows to partially inhibit the myostatin protein which in turn partially negates its influence on muscular growth at the genetic level. As a result this partial inhibition creates a window for a strong anabolic environment which can lead to net muscle gain....? Also, that is interesting than clen also acts as a myostatin inhibitor. I never knew that and I always considered the slight anabolic effect (if any) was attributed to its activity on the beta-3 receptors within the human body, but the effects are negligible due to humans not being heavily saturated with beta-3 receptors in comparison to other mammals.

I really need to do some research on myostatin. I kind of just ignored it because it was a protein associated at the genetic level and genetic engineering/therapy is astronomical in price and generally not completely understood.
 
Yes, in this case via Akirin-1/Mighty expression (which suppresses Myostatin). This is not the only known vector of myostatin modulation; increasing numbers of substances are known to affect myostatin (either its actual output, or its ability to function) via various known and unknown mechanisms. AAS is another (which is one reason I always taper up my doses), as is training (which is one reason I also taper up/periodise my training intensities), calorie/food intake, protein intake etc.
 
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