What it is
Follistatin is a natural protein that binds and neutralises several members of the TGF-beta family, most famously activin and myostatin. Myostatin is the body's brake on muscle growth, so anything that blocks it is of obvious interest for muscle-wasting diseases, and for bodybuilding.
The follistatin gene is spliced two ways, giving precursors called FST344 and FST317. Once the cell trims off the signal sequence, those become the secreted forms FST315 and FST288. FST315 is the form found mainly in the circulation, because it binds weakly to heparin on cell surfaces; FST288 binds tightly and acts locally in tissues.
"Follistatin-344" as a product name comes from the gene therapy literature, where FS344 is the gene construct delivered by a virus. Research vials sold under that name are something different: a protein you would inject from outside. That distinction is the key to reading the evidence.
How it works
Follistatin wraps around its target. With activin, two follistatin molecules envelop one activin molecule and stop it reaching its receptor. It binds myostatin, some bone morphogenetic proteins and other relatives in a similar way. With the myostatin brake released, muscle fibres grow larger.
Because follistatin also blocks activin, which has roles in the reproductive system, blocking it is not confined to muscle. The FS344 splice form was chosen for gene therapy because, in the words of the monkey study, it affects skeletal muscle but has only minimal effects on non-muscle cells.
What the research found
Animal studies
- Mice (Lee and McPherron 2001). Mice engineered to overproduce follistatin in skeletal muscle showed dramatic increases in muscle mass, comparable to mice with the myostatin gene knocked out. This was one of the studies that established follistatin as a myostatin inhibitor.
- Monkeys (Kota 2009). Cynomolgus macaques received the FS344 gene by an AAV1 vector injected into the quadriceps. The treated muscles showed pronounced and durable increases in size and strength, and long-term expression did not produce abnormal changes in the structure or function of key organs.
Human studies
- Becker muscular dystrophy (Mendell 2015). The only human trial is a gene therapy study. Six patients with Becker muscular dystrophy received AAV1.CMV.FS344 by direct injection into both quadriceps, at one of two vector doses. In the lower dose group, two patients improved their six-minute walk distance by 58 and 125 metres and one did not change. In the higher dose group, two improved by 108 and 29 metres and one did not improve. Muscle biopsies showed less fibrosis and larger fibres, and no adverse effects were reported.
That is six people, with no placebo group, receiving a one-time gene transfer that makes their own muscle cells produce follistatin locally for a long period. It says nothing direct about injecting a vial of follistatin protein under the skin, which would reach muscle through the bloodstream, be cleared, and need repeated dosing. We found no published human study of that approach.
Side effects reported in studies
The Becker trial reported no adverse effects in its six patients, and the monkey study found no organ abnormalities with long-term expression. Those findings apply to gene therapy delivered into muscle. For injected follistatin protein there are no human safety data. The theoretical concerns follow from its biology: activin and related proteins have roles well beyond muscle, including in reproduction, so blocking them systemically is not a muscle-only intervention. The related drug ACE-031, which also soaks up myostatin and its relatives, was stopped in children because of bleeding and blood-vessel side effects.
Follistatin-344 vs ACE-031
| Follistatin-344 | ACE-031 | |
|---|---|---|
| What it is | Natural binding protein | Engineered decoy receptor (ActRIIB-Fc) |
| Human data | Gene therapy in 6 Becker patients | Phase 1 in healthy women; phase 2 in Duchenne boys, stopped |
| Delivery in trials | Viral vector into muscle | Subcutaneous injection |
| Status | Investigational | Development discontinued |
For a broader look at what has been studied for muscle, see peptides for muscle growth and fat loss.
Status in the Philippines
No follistatin product, protein or gene therapy, is approved anywhere or registered with FDA Philippines. Vials labelled follistatin-344 are sold by research-chemical suppliers. For athletes, the WADA Prohibited List names myostatin-binding proteins such as follistatin under section S4, prohibited at all times.
Storage
Follistatin is a large glycoprotein and far less robust than a short peptide. Keep it cold, avoid repeated freezing and thawing, and do not leave it out through a Manila afternoon or a brownout. Once mixed, keep it at 2 to 8°C. Heat damage to a protein is not visible in the vial.
