Inhibiting Myostatin to increase your Height

We know it's possible to grow taller by inhibiting myostatin.  But how do we inhibit myostatin?  Myostatin helps regulate stem cell proliferation and differentiation(it inhibits it).  If we could inhibit myostatin we would benefit from enhanced stem cell proliferation and differentiation.  If you are doing Lateral Synovial Joint Loading, you want as much MSC proliferation and differentiation as possible.  If you are still naturally developing then inhibiting myostatin and nothing else may help you increase your stature. There are no products out right now that inhibit myostatin.  Are there natural ways to inhibit myostatin?  Can we design exercises? 

Caveolin-3 regulates myostatin signaling. Mini-review.

"Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduction and vesicular trafflicking. Loss of caveolin-3, resulting from dominant negative mutations of caveolin-3 causes autosomal dominant limb-girdle muscular dystrophy (LGMD) 1C and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-beta superfamily, negatively regulates skeletal muscle volume[It negatively regulates bone volume too]. Herein we review caveolin-3 suppressing of activation of type I myostatin receptor, thereby inhibiting subsequent intracellular signaling. In addition, a mouse model of LGMD1C has shown atrophic myopathy with enhanced myostatin signaling. Myostatin inhibition ameliorates muscular phenotype in the model mouse, accompanied by normalized myostatin signaling. Enhanced myostatin signaling by caveolin-3 mutation in human may contribute to the pathogenesis of LGMD1C. Therefore, myostatin inhibition therapy may be a promising treatment for patients with LGMD1C. More recent studies concerning regulation of TGF-beta superfamily signaling by caveolins have provided new insights into the pathogenesis of several human diseases." 

Now remember that TGF-beta is important in causing stem cells to differentiate into chondrocytes.  This means that caveolins are very important.  Caveolin-3 actually supresses myostatin reception.  Extraneous injection of Caveolin-3 may inhibit myostatin and increase stem cell differentiation.   

Here's a way to inhibit myostatin if you haven't been born yet... 

Myostatin gene knockdown through lentiviral-mediated delivery of shRNA for in vitro production of transgenic bovine embryos. 

"Myostatin is described as a negative regulator of the skeletal muscle growth. Genetic engineering, in order to produce animals with double the muscle mass and that can transmit the characteristic to future progeny, may be useful. In this context, the present study aimed to analyse the feasibility of lentiviral-mediated delivery of short hairpin RNA (shRNA) targeting of myostatin into in vitro produced transgenic bovine embryos. Lentiviral vectors were used to deliver a transgene that expressed green fluorescent protein (GFP) and an shRNA that targeted myostatin. Vector efficiency was verified through in vitro murine myoblast (C2C12) cell morphology after inductive differentiation and by means of real-time PCR. The lentiviral vector was microinjected into the perivitellinic space of in vitro matured oocytes. Non-microinjected oocytes were used as the control. After injection, oocytes were fertilized and cultured in vitro. Blastocysts were evaluated by epifluorescence microscopy. Results demonstrated that the vector was able to inhibit myostatin mRNA in C2C12 cells, as the transducted group had a less amount of myostatin mRNA after 72 h of differentiation (p < 0.05) and had less myotube formation than the non-transduced group (p < 0.05). There was no difference in cleavage and blastocyst rates between the microinjected and control groups. After hatching, 3.07% of the embryos exhibited GFP expression, indicating that they expressed shRNA targeting myostatin. In conclusion, we demonstrate that a lentiviral vector effectively performed shRNA myostatin gene knockdown and gene delivery into in vitro produced bovine embryos. Thus, this technique can be considered a novel option for the production of transgenic embryos and double muscle mass animals." 

Now it's possible to alter gene expression in fully developed adults too.  So perhaps this lentiviral vector can be used to alter stature in people already born.  

We can also block myostatin signaling... 

SB431542 treatment promotes the hypertrophy of skeletal muscle fibers but decreases specific force. 

"The small molecule inhibitor SB431542 inhibits activin type I receptors. The muscle growth-inhibitor myostatin binds to and signals via these receptors. The aim of this study was to test the hypothesis that SB431542 can inhibit myostatin-related Smad signaling and induce muscle growth in cultured C2C12 myotubes and increase growth and specific force in cultured Xenopus muscle fibers. The effect of SB431542 was assessed in vitro on C2C12 myotubes and ex vivo using mature Xenopus muscle fibers. SB431542 treatment reduced myostatin-induced C-terminal Smad2 phosphorylation and resulted in the formation of enlarged myotubes. However myogenin expression was unchanged, while p70 S6k phosphorylation at Thr389, total myosin heavy chain, and the rate of protein synthesis were all reduced. Mature Xenopus muscle fibers that were treated with SB431542 had a higher fiber cross-sectional area but decreased specific force production than control. SB431542 can initially antagonize myostatin signaling, but long-term unexpected signaling effects occur. Muscle fibers hypertrophy, but their specific force decreases compared to control." 

Two problems:  SB431542 did not have long-term benefits and we need to inhibit myostatin's effects in the bone not the muscle.  

Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression. 

"The cytokines of transforming growth factor beta (TGF-beta) and its superfamily members are potent regulators of tumorigenesis and multiple cellular events. Myostatin is a member of TGF-beta superfamily and plays a negative role in the control of cell proliferation and differentiation. We now show that myostatin rapidly activated the extracellular signal-regulated kinase 1/2 (Erk1/2) cascade in C2C12 myoblasts. A more remarkable Erk1/2 activation stimulated by myostatin was observed in differentiating cells than proliferating cells. The results also showed that Ras was the upstream regulator and participated in myostatin-induced Erk1/2 activation because the expression of a dominant-negative Ras prevented myostatin-mediated inhibition of Erk1/2 activation and proliferation. Importantly, the myostatin-suppressed myotube fusion and differentiation marker gene expression were attenuated by blockade of Erk1/2 mitogen-activated protein kinase (MAPK) pathway through pretreatment with MAPK/Erk kinase 1 (MEK1) inhibitor PD98059, indicating that myostatin-stimulated activation of Erk1/2 negatively regulates myogenic differentiation. Activin receptor type IIb (ActRIIb) was previously suggested as the only type II membrane receptor triggering myostatin signaling. In this study, by using synthesized small interfering RNAs and dominant-negative ActRIIb, we show that myostatin failed to stimulate Erk1/2 phosphorylation and could not inhibit myoblast differentiation in ActRIIb-knockdown C2C12 cells, indicating that ActRIIb was required for myostatin-stimulated differentiation suppression. Altogether, our findings in this report provide the first evidence to reveal functional role of the Erk1/2 MAPK pathway in myostatin action as a negative regulator of muscle cell growth." 

So inhibiting ActRIIb can also enhance cellular proliferation as can inhibiting Ras. 

Enhanced muscle growth by plasmid-mediated delivery of myostatin propeptide. 

"Myostatin is a member of the transforming growth factor beta (TGF-beta) superfamily that functions as a negative regulator of skeletal muscle development and growth. Myostatin blockade therefore offers a strategy for promoting muscle growth in livestock production without resorting to genetic manipulation. In this report, we examined the effect of myostatin inhibition by plasmid-mediated delivery of a mutant myostatin propeptide (MProD76A), a natural inhibitor of myostatin, on the growth performance of mice. A significant increase in skeletal muscle mass was observed after a single intramuscular injection of naked plasmid DNA encoding MProD76A into mice. Enhanced muscle growth occurred because of myofiber hypertrophy, but no cardiac muscle hypertrophy and organomegaly was observed in the mice after myostatin inhibition by plasmid-mediated MProD76A delivery. These results demonstrate a promising approach to enhancing muscle growth that warrants further investigation in domestic animals." 

Now this peptide may only inhibit myostatin in myofiber muscle and not bone.  

Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. 

"Myostatin inhibition is a promising therapeutic strategy to maintain muscle mass in a variety of disorders, including the muscular dystrophies, cachexia, and sarcopenia. Previously described approaches to blocking myostatin signaling include injection delivery of inhibitory propeptide domain or neutralizing antibodies. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a unique method of myostatin inhibition utilizing recombinant adeno-associated virus to overexpress a secretable dominant negative myostatin exclusively in the liver of mice. Systemic myostatin inhibition led to increased skeletal muscle mass and strength in control C57 Bl/6 mice and in the dystrophin-deficient mdx model of Duchenne muscular dystrophy. The mdx soleus, a mouse muscle more representative of human fiber type composition, demonstrated the most profound improvement in force production and a shift toward faster myosin-heavy chain isoforms. Unexpectedly, the 11-month-old mdx diaphragm was not rescued by long-term myostatin inhibition. Further, mdx mice treated for 11 months exhibited cardiac hypertrophy and impaired function in an inhibitor dose-dependent manner. CONCLUSIONS/SIGNIFICANCE: Liver-targeted gene transfer of a myostatin inhibitor is a valuable tool for preclinical investigation of myostatin blockade and provides novel insights into the long-term effects and shortcomings of myostatin inhibition on striated muscle." 

Now this adeno-associated virus seemed to inhibit myostatin everywhere(everywhere includes bone) so this has more promise. 

Trichostatin A induces follistatin a myostatin inhibitor.  

Inhibition of myostatin promotes myogenic differentiation of rat bone marrow-derived mesenchymal stromal cells. 

"Mesenchymal stromal cells (MSC) have been thought to be attractive candidates for the treatment of Duchenne muscular dystrophy (DMD), but the rate of MSC myogenesis is very low. Thus MSC treatment for DMD is restricted. Myostatin (Mstn), a negative regulator of myogenesis, is known to be responsible for limiting skeletal muscle regeneration. We hypothesized that inhibition of Mstn by using anti-Mstn antibody (Ab) would ameliorate the myogenic differentiation of MSC in vitro and in vivo. Methods MSC were isolated from rat bone marrow. Induced rat MSC (rMSC) were treated with various concentrations of anti-Mstn Ab. The expression of myogenic differentiation antigen (MyoD), myogenin and myosin heavy chain-type alpha (MHC-alpha) were estimated by immunofluorescence analysis and reverse transcription-polymerase chain reaction (RT-PCR). Adipogenic differentiation of rMSC inhibited by anti-Mstn Ab was evaluated by Oil Red O staining. The expression of dystrophin was detected 16 weeks after anti-Mstn Ab injection and rMSC transplantation by immunofluorescence staining, RT-PCR and Western blot. Motor function, serum creatine kinase (CK) and histologic changes were also evaluated. Results Five-azacytidine-mediated myogenic differentiation induced significant endogenous Mstn expression. Anti-Mstn Ab improved the expression of MyoD, myogenin and MHC-alpha and inhibited adipocyte formation. Sixteen weeks after transplantation, the inhibition of Mstn had improved motor function and muscle mass. In accordance with the increased motor function and muscle mass, dystrophin expression had increased. Furthermore, serum CK and centrally nucleated fiber (CNF) levels decreased slightly, suggesting specific pathologic features of the dystrophic muscle were partially restored. Conclusions Using anti-Mstn Ab, we found that inhibition of Mstn improved myogenic differentiation of rMSC in vitro and in vivo. A combination of Mstn blockade and MSC transplantation may provide a pharmacologic and cell-based strategy for the treatment of DMD." 

So there are anti-myostatin antibodies. There is some indication that aerobic exercise may inhibit myostatin... 

Myostatin Decreases with Aerobic Exercise and Associates with Insulin Resistance. 

"There is mounting evidence that skeletal muscle produces and secretes biologically active proteins or "myokines" that facilitate metabolic cross talk between organ systems. The increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Despite these intriguing findings, there have been few studies linking myostatin and insulin resistance. METHODS.: To explore this relationship in more detail, we quantified myostatin protein in muscle and plasma from 10 insulin-resistant, middle aged (53.1 +/- 5.5 years) men before and after 6 months of moderate aerobic exercise training (1200 kcal/wk at 40-55% peak VO2). To establish a case-effect relationship we also injected C57/Bl6 male mice with high-physiologic levels of recombinant myostatin protein. RESULTS.: Myostatin protein levels were shown to decrease in muscle (37%, P=0.042, n=10) and matching plasma samples (28.7 pre-training to 22.8 ng/ml post-training, P=0.003, n=9) with aerobic exercise. Furthermore, the strong correlation between plasma myostatin levels and insulin sensitivity (R2 = 0.82, P<0.001, n=9) suggested a cause-effect relationship that was subsequently confirmed by inducing insulin resistance in myostatin-injected mice. A modest increase (44%) in plasma myostatin levels was also associated with significant reductions in the insulin-stimulated phosphorylation of AKT (Thr308) in both muscle and liver of myostatin treated animals. CONCLUSIONS.: These findings indicate that both muscle and plasma myostatin protein levels are regulated by aerobic exercise and furthermore, that myostatin is in the causal pathway of acquired insulin resistance with physical inactivity." 

Exercise increases insulin sensitivity.  Is it the increase in insulin sensitivity that inhibits myostatin or something with the exercise itself?  Also, only myostatin in the muscle decreased; we don't know about the bone.  There is also evidence that resistance exercise inhibits myostatin too but does that include the bone or just the muscle..