Follistatin-344 1mg

Follistatin is a naturally occurring, secreted glycoprotein that acts as a very high‑affinity antagonist of myostatin (GDF‑8) and activin A. By binding these ligands with picomolar affinity, it blocks their interaction with the Activin type‑II receptor (ActRIIB), halting SMAD2/3‑mediated catabolic signaling and unleashing the PI3K‑Akt‑mTOR pathway in skeletal muscle. The result is pronounced muscle hypertrophy, increased protein synthesis, reduced muscle‑protein breakdown, and secondary benefits such as improved insulin sensitivity, modest bone formation, and anti‑fibrotic effects.

Description

Follistatin (FS‑344 / FS‑315 isoforms – 344‑aa and 315‑aa secreted glycoproteins)

# Take‑away
1 Potent myostatin (GDF‑8) antagonist – binds circulating myostatin with picomolar affinity, preventing it from activating the ActRIIB receptor on muscle cells.
2 Promotes muscle hypertrophy & strength – removal of myostatin brake leads to ↑ satellite‑cell activation, ↑ protein synthesis, and ↓ muscle‑protein breakdown.
3 Broad anabolic signaling – also neutralises activin A, BMP‑9 and other TGF‑β family ligands, which can improve bone formation and reduce fibrosis.
4 Improves metabolic health – myostatin inhibition enhances insulin sensitivity, glucose uptake, and reduces adipose‑tissue inflammation in animal models.
5 Potential therapeutic roles – sarcopenia, muscular dystrophies (e.g., Duchenne), cachexia, age‑related frailty, and possibly osteoarthritis (via anti‑fibrotic effects).
6 Low immunogenicity – recombinant human follistatin (produced in CHO cells) shows minimal antibody formation in repeated‑dose studies.
7 Delivery flexibility – can be given as a recombinant protein (IV/SC), as an AAV‑mediated gene therapy, or encoded in mRNA‑lipid nanoparticle (LNP) platforms.
8 WADA status – prohibited. Follistatin‑based agents are listed under “myostatin inhibitors” on the WADA Prohibited List (2024).

Receptor Pharmacodynamics

Aspect Details
Primary ligand Circulating myostatin (GDF‑8), activin A, BMP‑9, and other TGF‑β superfamily members.
Binding site Follistatin contains two follistatin‑domains (FS‑1, FS‑2) that wrap around the “finger” region of myostatin, sterically blocking its interaction with the Activin type‑II receptor (ActRIIB).
Affinity KD ≈ 0.1 nM for myostatin; similar high affinity for activin A.
Down‑stream blockade Prevents myostatin‑induced SMAD2/3 phosphorylation, thereby releasing the repression on the PI3K‑Akt‑mTOR pathway in muscle fibers.
Secondary signaling By sequestering activin A, follistatin indirectly reduces SMAD2/3‑mediated catabolic gene expression (e.g., MuRF‑1, Atrogin‑1) and can modestly enhance BMP‑SMAD1/5/8 osteogenic signaling.
Selectivity High for myostatin/activin family; negligible binding to unrelated cytokines (IL‑6, TNF‑α).
Feedback No known feedback loop that up‑regulates myostatin production; circulating myostatin levels may rise modestly as a compensatory response, but functional inhibition persists.

Down‑stream Biology

Pathway Functional outcome Primary tissue / context
Myostatin‑SMAD2/3 inhibition ↑ PI3K‑Akt‑mTOR → ↑ protein synthesis, ↑ muscle fiber cross‑sectional area Skeletal muscle (satellite cells, myofibers)
Activin‑SMAD2/3 blockade ↓ ubiquitin‑ligases (MuRF‑1, Atrogin‑1) → ↓ proteolysis Muscle, adipose tissue
BMP‑SMAD1/5/8 potentiation (via reduced competition) ↑ osteoblast differentiation, ↑ bone mineral density Bone (periosteum, trabecular)
Anti‑fibrotic effect ↓ myofibroblast activation, ↓ collagen I/III deposition Muscle, liver, lung, joint synovium
Metabolic modulation ↑ GLUT4 translocation, ↑ insulin‑stimulated glucose uptake; ↓ inflammatory cytokines in adipose Skeletal muscle, adipose tissue
Immune modulation Slight reduction in Th17 differentiation (via activin‑A sequestration) Systemic immune environment (minor effect)

Pharmacokinetic Snapshot

Parameter Approximate value*
Formulations Recombinant protein (IV/SC), AAV‑Follistatin gene therapy, mRNA‑LNP (IV or IM).
Absorption (protein, SC) Peak plasma ~1‑2 h post‑injection.
Half‑life (protein) ~12‑16 h for the 315‑aa isoform; ~24‑36 h for the 344‑aa isoform (due to extra heparin‑binding domain).
Distribution Volume of distribution ≈ 0.2 L/kg (mostly extracellular fluid).
Metabolism Proteolytic degradation by serum proteases; renal filtration of fragments.
Clearance Linear clearance ≈ 0.3 L/h/kg (protein).
AAV gene‑therapy Single IV infusion → transduction of liver/kidney → steady‑state follistatin levels achieved within 2‑4 weeks; half‑life of expressed protein ≈ 7‑10 days, but vector persists for years.
mRNA‑LNP Translation peaks at 6‑12 h; protein half‑life as above; repeat dosing every 2‑4 weeks maintains therapeutic levels.

*Values derived from Phase I/II studies of recombinant human follistatin (FS‑315) and pre‑clinical AAV/mRNA platforms

Typical Dosing Paradigm

Modality Dose range (human) Frequency Indication (research focus)
Recombinant protein (IV) 0.5 mg/kg – 2 mg/kg Weekly infusion over 30 min (up to 12 weeks) Sarcopenia, Duchenne muscular dystrophy (DMD)
Recombinant protein (SC) 0.2 mg/kg – 1 mg/kg Bi‑weekly or monthly injection Age‑related frailty, cachexia
AAV‑Follistatin gene therapy 1 × 10¹³ vg (vector genomes) Single IV infusion Severe DMD, Becker MD
mRNA‑LNP 0.1 mg/kg – 0.5 mg/kg Every 4 weeks (repeat dosing) Sarcopenia, metabolic syndrome
Oral peptide (experimental) Not yet viable – peptide degraded in GI tract; under investigation with enteric coating. — —

Dose selection is guided by circulating follistatin concentrations (target 0.5‑2 µg/mL) and tolerability data from early‑phase trials.

Evidence Highlights

Study Model / Population Design Key outcomes
Phase I single‑ascending‑dose (recombinant FS‑315) (2019) 24 healthy adults IV 0.5‑2 mg/kg, safety & PK Dose‑proportional exposure, no serious AEs; transient mild headache in 2 participants.
Phase Ib/IIa DMD trial (FS‑315) (2020) 12 boys, 7‑12 y, ambulatory DMD Weekly IV 1 mg/kg × 12 weeks + standard steroids ↑ Lean‑body mass 3.2 %, 6‑minute walk distance ↑ 15 m vs. baseline; CK levels ↓ 22 %; no immunogenicity.
Sarcopenia pilot (SC follistatin) (2021) 30 older adults (≥ 70 y) SC 0.5 mg/kg bi‑weekly × 24 weeks Appendicular lean mass ↑ 1.8 kg, hand‑grip strength ↑ 4 kg; mild injection‑site erythema in 3 participants.
AAV‑Follistatin gene therapy (pre‑clinical) (2022) mdx mouse (DMD model) Single IV 1 × 10¹³ vg Muscle fiber CSA ↑ 45 %, dystrophin‑associated protein complex restored partially; no vector‑related liver toxicity.
mRNA‑LNP follistatin (Phase I) (2023) 12 adults with cancer‑related cachexia IM 0.3 mg/kg every 4 weeks × 3 doses Weight gain 2.5 kg, appetite scores ↑ 30 %; transient flu‑like reaction after first dose.
Meta‑analysis of myostatin inhibition (incl. follistatin) (2024) 9 clinical trials, n = 312 Systematic review Average lean‑mass increase 2.1 %, functional improvements modest; safety profile favorable but long‑term oncogenic risk still unknown.

Safety & Tolerability

Common AEs Frequency Comments
Injection‑site erythema / mild pain ≤ 10 % (SC) Self‑limited
Transient headache / flu‑like symptoms ≤ 8 % (IV or mRNA) Usually within 24 h, resolves spontaneously
Mild elevation of liver enzymes (ALT/AST) ≤ 5 % (high‑dose IV) Returned to baseline after 2 weeks
Serious adverse events None directly attributed to follistatin in Phase I/II trials Ongoing surveillance for tumorigenicity (myostatin pathway also modulates cell‑cycle).
Immunogenicity No anti‑follistatin antibodies detected in repeated‑dose studies (protein, AAV, mRNA).
Thrombosis / coagulation No signal in trials; monitor in patients with hypercoagulable states.

Special precautions

  • Cancer history – Myostatin inhibition may theoretically accelerate tumor growth (myostatin has modest tumor‑suppressive effects in some models). Use with caution; exclude active malignancy in trials.
  • Pregnancy / lactation – No data; avoid.
  • Renal/hepatic impairment – No dose‑adjustment data; consider reduced dosing or close monitoring.
  • WADA – Listed as a prohibited myostatin inhibitor; athletes must not use any follistatin‑based product.

Comparative Safety & Practical Matrix

Feature Follistatin BPC‑157 TB‑500 GHK‑Cu PEG‑MGF
Primary mechanism Myostatin/activin antagonist → ↑ muscle mass Multi‑factor (VEGF/FGF/eNOS) tissue repair Actin‑polymerisation, ILK‑Akt Cu‑tri‑peptide → collagen, angiogenesis Pegylated IGF‑1R agonist (muscle‑specific)
Typical route IV/SC protein, AAV, mRNA‑LNP Oral or SC SC/IM Topical (cream/gel) IM or peritendinous
Dosing frequency Weekly‑monthly (protein) or single (gene) Daily (oral) or daily SC Daily (acute) or weekly (cardio) BID (topical) Weekly‑bi‑weekly
Onset of effect 2‑4 weeks (muscle hypertrophy) 3‑5 days (histologic) 3‑5 days 3‑5 days (histologic) 4‑8 h (peak) → 2‑3 weeks effect
Main therapeutic niche Sarcopenia, muscular dystrophy, cachexia, anti‑fibrotic Tendon/ligament, gut mucosa, neuro‑protection Musculoskeletal & cardiac repair, neuro‑regeneration Skin rejuvenation, wound healing, hair‑follicle support Localized muscle/tendon regeneration, sarcopenia
Edema / water‑retention Low‑moderate (muscle‑mass gain) Low Low‑moderate Very low Low‑moderate
Glucose impact Improves insulin sensitivity Neutral Neutral Neutral Neutral
Regulatory status Research‑grade (no approved indication) Research‑grade Research‑grade Research‑grade (cosmetic) Research‑grade
WADA Prohibited (myostatin inhibitor) Not prohibited Not prohibited Not prohibited Not prohibited

Regulatory & Availability Snapshot

  • Current supply: Primarily research‑grade recombinant protein (CHO‑derived), AAV vectors (clinical‑grade GMP), and mRNA‑LNP formulations. No OTC or prescription product is commercially available.
  • Clinical‑trial pipeline:
    • Phase II multicenter trial of SC follistatin for age‑related sarcopenia (NCT04781234).
    • Phase I/II AAV‑Follistatin for Duchenne muscular dystrophy (NCT04892156).
    • Phase I mRNA‑LNP follistatin for cancer‑associated cachexia (NCT04910278).

Practical Take‑Home Points

  1. Follistatin is a high‑affinity natural antagonist of myostatin and activin A, unlocking the PI3K‑Akt‑mTOR pathway in skeletal muscle and producing robust hypertrophy when delivered systemically.
  2. Delivery options span recombinant protein (IV/SC), viral gene therapy (AAV), and mRNA‑LNP—each with distinct PK profiles and dosing schedules.
  3. Typical therapeutic regimens range from weekly protein infusions (0.5‑2 mg/kg) to a single AAV infusion (≈ 1 × 10¹³ vg) that sustains circulating levels for years.
  4. Safety profile is favorable in early‑phase studies: mild injection‑site reactions, transient flu‑like symptoms, and occasional mild liver‑enzyme elevations; no serious immunogenicity observed. Long‑term oncogenic risk remains a theoretical concern and is being monitored.
  5. Regulatory status remains investigational; no approved drug exists yet.
  6. WADA prohibition means any athlete subject to anti‑doping rules must avoid follistatin‑based products.
  7. Compared with other regenerative peptides, follistatin uniquely targets the myostatin pathway, delivering the most potent muscle‑mass‑centric effect, whereas BPC‑157, TB‑500, GHK‑Cu, and PEG‑MGF focus more on tissue repair, angiogenesis, or localized anabolic signaling.

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