Downstream target of TGF-beta, fibroblast to myofibroblast conversion.
TGF-beta is a protein that sticks to connective tissue in an inactive form and is activated and released by shear stress, tension, at least some wavelengths of light, and many other things. The activated TGF-beta then interacts with a few different TGF-beta receptors which can do a very wide array of things in various kinds of cells. One of the things it can do is convert fibroblasts to myofibroblasts.
Myofibroblasts are, generally, a temporary kind of muscle cell (muscle meaning they contract). They adhere to connective tissue and then build a scaffold within the cell to contract and pull the connective tissue they’re attached to together. Myofibroblasts are meant to be temporary, they pull wounded tissue closed and the connective tissues are enzymatically glued back together with something like LOX. They should exist as myofibroblasts for about 6 hours if I remember right, then they either apoptose or they convert back to fibroblasts. The problem often arises in fibrotic tissue that they remain active for much longer in a self sustaining, which drives aberrant fibrosis and contracture (shortening of tissue).
There are several small molecule interventions that interrupt the conversion of fibroblasts to myofibroblasts, there are also small molecule interventions for eliminating persistent myofibroblasts.
They have similar problems related to all substances that might be useful for PE, there isn’t a good way for local administration and while the penis is a unique tissue, it’s not that unique, so administering something systemically would have systemic effects.
TGF-beta is a very integrated protein, it’s part of the core mechanisms that regulate multicellular structuring.
Dealing with myofibroblasts is a more downstream mechanism, so the side effects of modulating it would probably be more minimal.
The penis enlargement plateau might be caused solely by the accumulation of persistent myofibroblasts, or just an upregulation of sensitivity of fibroblasts to TGF-beta in its active form, or just the increased expression of inactive TGF-beta.
I have inadvertently tested 1 substance that prevents the conversion of fibroblasts to myofibroblasts already, the test was motivated by weak, but intriguing, correlations that showed up in some data, not studies into the activity of the substance. It didn’t have a noticeable impact on the growth rate.
I’ve also tested several antifibrotics which way or may not individually have anything to do with fibroblast to myofibroblast conversion or myofibroblast persistence. Again no gains noticed.
I’m thinking about moving on to testing low risk epigenetic modulating drugs, since there’s reason to believe that you can simply prevent the phenotype change and get rid off persistent myofibroblasts on that level with limited systemic risk. Local administration again is a problem, the HDACis I have on hand are rapidly metabolized. The problem with HDACis is that when used as an antifibrotic they can increase calcification of existing fibrotic tissue (probably because they interfere with the matrix metalloproteinases). I don’t know if that would be an issue if the HDACis were cycled, but calcification of the penis is definitely not something we want to happen.
Maybe this post will get some fruitful discussion going on the deeper mechanics of PE and the plateau. I’d like to know if anyone has any ideas about the relationship between myofibroblasts and PE. The relation between myofibroblasts and PE I’m presenting is just speculative and hypothetical. Since I don’t have tissue samples from men’s penises before and after they plateau on gains, speculation is the best I can do right now.
Starting: 7"bplx5.2" 2017 (shrunk from disuse)(originally 8"bplx4.5", gained to 9"bplx6")
Current: 9.0"bplx6.125" 2020
Goal: 11.5"bplx7" 2021.