Wednesday, April 21, 2010

Growing Taller by inhibiting the myostatin gene?

It is well known in the bodybuilding community that Myostatin is a gene that inhibits muscle mass.  Turns out it has properties on height gain as well.  A mutation in the myostatin receptor and a mutation in Myostatin will have positive effects as well.  There have been a couple of people born without the presence of Myostatin.

Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. 

"Myostatin (GDF-8) is a member of the transforming growth factor-beta (TGF-beta) superfamily that is highly expressed in skeletal muscle, and myostatin loss-of-function leads to doubling of skeletal muscle mass. Myostatin-deficient mice have been used as a model for studying muscle-bone interactions, and here we review the skeletal phenotype associated with altered myostatin signaling. It is now known that myostatin is a key regulator of mesenchymal stem cell proliferation and differentiation[More proof that LSJL works by causing the differentiation of mesenchymal stem cells into chondrocytes], and mice lacking the myostatin gene show decreased body fat and a generalized increase in bone density and strength. The increase in bone density is observed in most anatomical regions, including the limbs, spine, and jaw, and myostatin inhibitors have been observed to significantly increase bone formation. Myostatin is also expressed in the early phases of fracture healing, and myostatin deficiency leads to increased fracture callus size and strength. Together, these data suggest that myostatin has direct effects on the proliferation and differentiation of osteoprogenitor cells, and that myostatin antagonists and inhibitors are likely to enhance both muscle mass and bone strength." 

It doesn't mention that myostatin has an impact on cartilage and chondrocytes but if it has impacts on mesenchymal stem cell proliferation than at the bare minimum it increases the number of MSCs available for chondrogenic differentiation.

"Myostatin circulates in the blood in a latent form bound to a propeptide, which gets cleaved by BMP1/Tolloid matrix metalloproteinase releasing the active form. Follistatin and follistatin–related gene (FLRG) are other proteins that can bind and inhibit the activity of myostatin by maintaining its latency2,5. Active myostatin binds to its receptor, the type IIB activin receptor (ActRIIB), with high affinity and regulates the expression of its target genes through a TGF-β signaling pathway. Recent studies also show that myostatin can activate the p38 MAPK, Erk1/2, and Wnt pathways[possible pathways that can indirectly affect myostatin's inhibition of height growth]" 

So you can also inhibit myostatin by inhibiting BMP1, increasing the levels of follistatin, inhibiting type IIB activin, and by preventing the effects of Myostatin in the pathways it triggers like the MAPK or Wnt signaling pathways.

The scientists speculate that the effect on bone may be due to an indirect effect based on muscle mass but the degree of adaption is just too great for it to be an effect of muscle mass alone.

SNPs in the myostatin gene of the mollusk Chlamys farreri: association with growth traits. 

"Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily which negatively regulates growth of muscle tissue. In this study, 103 cultivated Chlamys farreri individuals were screened for polymorphisms in the MSTN gene using PCR-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods. Two mutations were found: A/G at position 327 in exon 2, which caused an amino acid change from Thr to Ala (Thr305Ala), and C/T at position 289 in exon 3, which caused an amino acid change from Cys to Arg (Cys422Arg). One way ANOVA of the SNPs and growth traits showed that genotype GG of primer M5 had significantly higher body mass, soft-tissue mass, adductor muscle mass, shell length, shell height, absolute growth rate of shell height and body mass than those of genotype AG and AA (P<0.05). Genotype frequencies of genotype AA, AG and GG were 68.94%, 27.18% and 3.88%, respectively. The results present evidence that the C. farreri MSTN gene may be selected as a candidate gene for these growth traits." 

Essentially the mollusks that had Myostatin inhibition(or specific polymorphisms within the Myostatin gene) were taller than those who were able to express Myostatin. 

Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume. 

"Myostatin (GDF-8) is a negative regulator of skeletal muscle growth and mice lacking myostatin show increased muscle mass. We have previously shown that myostatin deficiency increases bone strength and biomineralization throughout the skeleton, and others have demonstrated that myostatin is expressed during the earliest phase of fracture repair. In order to determine the role of myostatin in fracture callus morphogenesis, we studied fracture healing in mice lacking myostatin. Adult wild-type mice (+/+), mice heterozygous for the myostatin mutation (+/-), and mice homozygous for the disrupted myostatin sequence (-/-) were included for study at two and four weeks following osteotomy of the fibula. Expression of Sox-5 and BMP-2 were significantly upregulated in the fracture callus of myostatin-deficient (-/-) mice compared to wild-type (+/+) mice at two weeks following osteotomy. Fracture callus size was significantly increased in mice lacking myostatin at both two and four weeks following osteotomy, and total osseous tissue area and callus strength in three-point bending were significantly greater in myostatin -/- mice compared to myostatin +/+ mice at four weeks post-osteotomy. Our data suggest that myostatin functions to regulate fracture callus size by inhibiting the recruitment and proliferation of progenitor cells in the fracture blastema. Myostatin deficiency increases blastema size during the early inflammatory phase of fracture repair, ultimately producing an ossified callus having greater bone volume[bone volume includes height] and greater callus strength. While myostatin is most well known for its effects on muscle development, it is also clear that myostatin plays a significant, direct role in bone formation and regeneration." 

Perhaps if Myostatin was inhibited pre-limb lengthening surgery.  The bone could be stretched by more than one mm a day. 

"The [fracture healing] process can be separated into three general phases: an initial inflammatory phase, a chondrogenic phase, and an osteogenic phase. The inflammatory phase is characterized by increased expression of GDF8[GDF8 is Myostatin], BMP2[BMP-2 helps initial chondrogenic differentiation, however BMP-2 is not enough to induce chondrogenic differentiation], and Wnt-5A, the chondrogenic phase by elevated expression of GDF5[GDF5 enhances extracellular matrix production], TGFβ2,3[TGF-Beta3 Is capable of inducing chondrogenic differentiation], and beta-catenin[Beta-Catenin can be induced by BMP-2 so this is expected], and the osteogenic phase by expression of BMP3,4,7,8, and Frizzled. The role of early GDF8 (myostatin) expression in the callus during the inflammatory phase of fracture healing has, however, been difficult to interpret since this factor is most well known for its effects on myogenesis. It is now known that the receptor for myostatin is expressed in bone-marrow derived stromal cell, and that myostatin can stimulate adipogenic differentiation in mesenchymal stem cells whereas its absence increases osteogenic differentiation. Myostatin regulates myogenic differentiation in part by suppressing the expression of myogenic factors such as MyoD, but it also inhibits myoblast proliferation by increasing levels of p21"

So Myostatin seems to be involved in the stem cell phase rather than at later stages.  So inhibiting myostatin will increase height mainly as a result of increasing stem cell proliferation.  So the earlier myostatin can be inhibited the better.  Probably why Testosterone and Creatine and other Myostatin inhibitors don't increase height that much as much of the stem cells are already differentiated into chondrocytes.

So, inhibiting Myostatin may augment height gain if used in conjunction with methods involving stem cells but after early development Myostatin increases effectiveness as a lot of the stem cells have already differentiated into chondrocytes.

Myostatin may have a direct inhibitory effect on Sox9.  Remember though that you want more Beta-Catenin than Sox9 to maximize height growth.

Myostatin (GDF-8) inhibits chondrogenesis and chondrocyte proliferation in vitro by suppressing Sox-9 expression.

"Here, we investigate a possible direct role for myostatin in chondrogenesis. First, we examined the effects of myostatin on the proliferation of bone marrow stromal cells (BMSCs) and epiphyseal growth plate (EGP) chondrocytes (EGPCs) isolated from myostatin-deficient mice. Results show that myostatin deficiency is associated with a significant (P < 0.001) increase in proliferation of both BMSCs (+25%) and EGPCs (+35%) compared with wild-type cells. Next, we examined the effects of myostatin treatment on chondrogenic differentiation of BMSCs. These experiments show that myostatin treatment starting at either 0 or 48 h induces a significant decrease in collagen type II protein synthesis by 31% (P < 0.001) and 25% (P < 0.05), respectively. Real-time PCR reveals significant (P < 0.01) down regulation of Sox9 mRNA expression with 10 and 100 ng/ml treatments. Together, these findings suggest that myostatin has direct effects on chondrogenesis, and may, therefore, represent a potential therapeutic target for improving bone repair."

So Myostatin directly affects the cells involved in height.

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