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03.03.2019

New follistatin analogue makes muscles 19 percent larger in a week

Danish researchers have developed a drug that deactivates the muscle growth inhibiting protein myostatin, but does not have the side effect that hangs like a dark shadow over current myostatin research. When the Danes gave lab animals a modified verrsion of follistatin for a week, their muscle mass increased by as much as 19 percent.

Follistatin
The research on myostatin inhibitors is still ongoing, but has been delayed by the discovery that at least one type of myostatin inhibitors has the side effect of increasing the production of red blood cells, as a result of which blood viscosity may increase dangerously. Then we are talking about synthetic type IIA and IIB activin receptors. These substances deactivate myostatin. How these substances increase the production of red blood cells is not exactly known.

Study
That is why the Danes, who are connected to Aarhus University Hospital, went looking for another myostatin inhibitor and decided to modify the follistatin molecule. Follistatin is a protein that muscle cells manufacture, which controls the effect of myostatin by preventing myostatin from interacting with its receptors.

When the Danes changed the follistatin molecule, they did not start from regular follistatin, but from the deviant follistatin analogue FST-dHBS. [J Pharmacol Exp Ther. 2018 Aug;366(2):291-302.] And this mutant analogue they fused with another protein fragment: the Fc region of the IgG molecule.

Results
In test tubes, the modified follistatin molecule neutralized activin A and B, myostatin and GDF11 - just like unmodified follistatin.

Administering regular follistatin is not efficient. The substance [FST315] disappears from the bloodstream at lightning speed. However, after injections with the modified follistatin molecule [FST-dHBS-hFc] the level of the substance reached impressive levels. In addition, one week after an injection with a large dose the modified molecule [FST-dHBS-mFc] was still detectable in mice's blood.

When the researchers treated mice with the modified follistatin molecule for a week, their body weight increased by 11 percent; the weight of their gastrocnemius increased by 19 percent. The new molecule had a greater anabolic effect than ActRIIA-mFC. [ActRIIA = activin type IIA receptor]

During this week, the Danes injected the mice 3 times with the modified follistatin molecule in their small intestine. This suggests that this molecule may even be active orally. The dose was 10 milligrams per kilogram of body weight. Here you can read how to calculate the human equivalent of that dose.

Unlike ActRIIA-mFC, the new follistatin analogue had no effect on the red blood cells and the blood's viscousness.

Conclusion
"FST-DHBS-mFc represents a molecule in the activin receptor signaling pathway class that increases muscle and bone mass without affecting red blood cell count or hematocrit or hemoglobin levels", summarize the researchers.

"This opens up the possibility of activin receptor signaling pathway therapy in patients with normal or high hematocrit, and it places FST-DHBS-mFc in a unique position among other candidate drugs that interfere with the pathways of the 3 pivotal ligands: activin A, myostatin, and GDF11."

Source:
FASEB J. 2019 Feb 13:fj201801969RR. doi: 10.1096/fj.201801969RR. [Epub ahead of print].

More:
One dose of myostatin inhibitor bimagrumab results in permanent muscle mass increase 28.11.2017
Decorin - myostatin inhibitor and follistatin booster - is key factor in muscle growth 19.11.2014
Animal study: a year of growth after just one anti-myostatin gene treatment 16.06.2013

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