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A little while back, I covered an in-depth study that identified the first mechanism by which the molecule ergine improves mitochondrial function. I won't rehash all the signs here, but in general, the researchers show one mechanism by which exercise might improve mitochondrial function by increasing the activity of an enzyme called MPST. This enzyme, when appropriately active, improves mitochondrial function, and this enzyme is stimulated by ergine as well. So, they ended up doing experiments with supplementation as well. Anyway, I'll leave the specifics of that video; it'll be linked for you.
However, in that video, I mentioned that I didn't report this data, but the researchers also showed an effect of exercise on the ergine transporter, the protein that allows ergine into the cell through a mitochondria-centric mechanism. I left that out because it's complex enough, although I may cover it in future work. Guess what? This is that future work.
The idea here is that mitochondria are heavily influenced by a master protein called PGC1 alpha. This protein controls if we generate new mitochondria, for example; it's extremely important. So, what the researchers of this study did was exercise mice and then remove some of their muscle tissue to test for the gene expression of the PGC1 alpha gene, the gene that produces the PGC1 alpha protein. Here is the data: on the vertical axis, we see the amount of PGC1 alpha gene expression. The higher the bar, the more of the gene is being transcribed for later protein production, since genes are transcribed to messenger RNA molecules and then converted by translation to proteins.
As you can see at baseline, that's before exercise, and then over time, gene reading or expression increases over 30, 60 minutes and is even still elevated at 2 to 4 hours. This isn't news; we've known that PGC1 alpha is stimulated by exercise. But what is news is this: on the left, we see the same PGC1 alpha data that we just went over. On the right, we see a gene called SLC22A4, or more easily understood, the ergine transporter. The transporter allows ergine into the cells of the body.
So, you might see the connection that the researchers were interested in. First, PGC1 alpha gene expression rises, then the ergine transporter gene expression rises. Is there a connection? To test this further, they generated mice that overexpress PGC1 alpha, meaning they didn't do an experiment like in the movie "The Fly" and poof, a mouse appeared. They either bred these mice or did an experiment known as electroporation to force the gene into the muscle tissue of these mice. I believe it was the former; however, either way, these mice have muscle cells that read or express the PGC1 alpha gene more than normal.
We see that here: the WT is the wild type or unedited normal mice, and the MCK PGC1 alpha are the mice with greater expression of the gene. As we see, the red box and whisker plot is many folds higher, indicating more expression. To be fair, they should include the protein measures, which they did not do.
Now, what happened to the ergine transporter gene? Voila! The transporter gene is expressed more in these high PGC1 alpha expressing mice, and we even see the protein measurements on the right. That is called a western blot, and the pink there is called a loading control, in this case, a Ponceau stain. The point is both gene and protein are more abundant.
Okay, great, but having more transporter on the cell membrane is certainly useful. But does that actually mean more ergine, the active molecule itself, is ending up in the muscles? Well, see for yourself. The reddish bar is the ergine found in the tissue; it's clearly more. However, I do have some concerns with these data. Look at the amount of extra gene expression of PGC1 alpha and look at the amount of increased ergine. Our end result is an 18 times increase in PGC1 alpha gene expression and only a 30% increase in ergine.
Is this relevant? For that, we need measures of protein because high gene expression can sometimes lead to unexpectedly less protein production, which would actually make the argument more convincing. Because if humans go exercising, how much of an increase in PGC1 alpha will they actually experience? 50%? If it's 50%, these results might not translate well. There are some questions that need to be answered here, but assuming these results pan out and PGC1 alpha truly does control, at least to some degree, tissue ergine concentrations, how does it do that?
Well, PGC1 alpha, the protein, is a co-regulator of gene expression. Essentially, it binds to proteins called transcription factors and allows them to read genes inside the nucleus of your cells. If PGC1 alpha protein is more abundant, which is an educated guess considering my earlier critiques, then it could bind transcription factors responsible for the reading of the ergine transporter gene, and more transporters are then created, allowing more ergine into the cell.
Another possibility is that PGC1 alpha may bind inhibitory transcription regulators, meaning proteins that would disallow the ergine transporter from being expressed. PGC1 alpha may negatively regulate these inhibitors, thereby stopping them from their criminal acts, or less dramatically, simply stopping their stopping of ergine transporter expression. There are many possibilities. It's also possible the mechanism is not directly due to PGC1 alpha and may be due to some other protein that it regulates, which also changes when PGC1 alpha is highly expressed.
These are the kinds of answers that this study doesn't answer. However, if you'd like to have a more complete breakdown of this study, including how ergine positively affects your mitochondria, check out my video on the topic right here. I hope that you enjoyed nerding out with me; I did with you. [Music]