Myostatin regulation with rna?
Ok so there's been bits of talk here and there about gene doping and some gene projects but I feel it's time we give one a shot. The idea is fairly simple. See if we can down-regulate myostatin via rna interference or other fairly harmless methods. I'd rather avoid viral vectors for now as they are tricky and permanant. I want this to be a temporary thing. Something that will interfere with the genetic pathways for a short while and then eventually either be broken down or be treatable with a counter agents to turn it off. I felt like rna interference would be ideal as you could use a small dosage so the affect could be fairly localized as once the rna is in use it shouldn't move anywhere. Or a larger dose could spread but eventually be broken down and allow normal function again.
That's the plan. Thoughts?
Comments
Whatever you do, I'd do it locally...
Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) amino acid residues. Its total molecular weight is 25.0 kDa. The protein is made in an inactive form. For it to be activated, a protease cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the now-active COOH-terminal dimer.
Myostatin binds to the activin type II receptor, resulting in a recruitment of a coreceptor called Alk-3 or Alk-4. This coreceptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMADfamily - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation. When applied to myoblasts, myostatin inhibits their differentiation into mature muscle fibers.
Recently, myostatin has also been shown to inhibit Akt, a kinase that is sufficient to cause muscle hypertrophy, in part through the activation of protein synthesis. However, it is notable that Akt does not responsible for all of the observed muscle hyperthrophic effects which are mediated by myostatin inhibition[7
TL:DR myostatin is a protein dimer encoded by the gene MSTN. Once active it binds to the ACVR2B protein and causes muscle growth to be suppressed.
So they've identified a mutant that can be controlled by microRNA. When that gene is transcribed into mRNA there's a bit at the end, part that doesn't get encoded that is a target for the miRNA and inhibits translation. This isn't super helpful for us since that would mean adding in a gene to humans which is tricky. What'd be easier is look at either the MSTN or ACVR2B sequence and decide which is better for the RNA interference and then design a miRNA that would interfere with it. This is a super temporary thing thought since as soon as you transcribe more mRNA the blocked ones become irrelevant. So we need to interfere with whatever causes MSTN to be transcribed in the first place. Which my guess may be PPAR delta
A myostatin inhibitor has been talked about a lot but there might be a few other targets that might be easier to pull off (like the PPAR-delta). I've collected a small list of potentials. I don't want to derail the thread though. I could make a new thread for general discussion of feasibility if you think that is wise.
They have some proprietary techniques that are laid bare in these instruction manuals....err...patents http://patents.justia.com/assignee/moderna-therapeutics
One of them is supposed to help us. I'll start digging through them in the morning.