Description
MOTS‑c 10mg
| # | Key point |
|---|---|
| 1 | Endogenous regulator of metabolic homeostasis – binds to the cell‑surface receptor α‑Klotho/FGFR1 complex and activates AMPK‑dependent pathways. |
| 2 | Improves insulin sensitivity, glucose disposal and lipid oxidation in rodents and early‑phase human studies. |
| 3 | Enhances exercise capacity & mitochondrial biogenesis via PGC‑1α up‑regulation and increased NAD⁺/SIRT1 activity. |
| 4 | Anti‑ageing signals – reduces systemic inflammation, improves endothelial function, and extends health‑span in mouse models of diet‑induced obesity and premature aging. |
| 5 | Therapeutic niches under investigation – type‑2 diabetes/pre‑diabetes, obesity, sarcopenic obesity, age‑related metabolic decline, and possibly cardiovascular protection. |
| 6 | Low immunogenicity – being an endogenous peptide, repeated dosing in humans has shown no anti‑MOTS‑c antibodies. |
| 7 | Delivery formats – synthetic peptide (sub‑cutaneous injection), peptide‑loaded biodegradable microspheres, and emerging oral‑stable analogues (e.g., cyclized or PEG‑conjugated forms). |
Receptor Pharmacodynamics
| Aspect | Details |
|---|---|
| Primary target | α‑Klotho/FGFR1 heterodimer on skeletal‑muscle, adipose, and hepatic cells. Binding promotes FGFR1 autophosphorylation. |
| Binding site | MOTS‑c interacts with the extracellular Ig‑like domain of FGFR1; α‑Klotho acts as a co‑receptor that stabilizes the complex. |
| Affinity | Reported Kd ≈ 0.5 nM for the α‑Klotho/FGFR1 complex (SPR data from recombinant proteins). |
| Down‑stream blockade/activation | Activates AMPK → ACC phosphorylation → ↑ fatty‑acid oxidation. Stimulates PI3K‑Akt‑mTOR modestly, improving glucose uptake. Up‑regulates PGC‑1α and NRF‑1, driving mitochondrial biogenesis. |
| Selectivity | High for the α‑Klotho/FGFR1 axis; negligible binding to unrelated RTKs (EGFR, PDGFR). |
| Feedback | Chronic administration can raise circulating FGF‑21 levels, a secondary metabolic hormone, but no compensatory increase in endogenous MOTS‑c expression has been reported. |
Down‑stream Biology
| Pathway | Functional outcome | Main tissues / context |
|---|---|---|
| AMPK‑ACC | ↑ fatty‑acid β‑oxidation, ↓ hepatic gluconeogenesis | Liver, skeletal muscle, adipose |
| PI3K‑Akt‑GLUT4 | ↑ insulin‑stimulated glucose uptake | Skeletal muscle, adipocytes |
| PGC‑1α/NRF‑1 | ↑ mitochondrial number & oxidative capacity | Muscle, heart, brown adipose |
| SIRT1‑NAD⁺ | Improves cellular stress resistance, DNA repair | Systemic |
| FGF‑21 secretion | Enhances lipolysis, improves lipid profile | Liver |
| Anti‑inflammatory signaling | ↓ NF‑κB activation, ↓ circulating IL‑6/TNF‑α | Endothelium, immune cells |
| Vascular tone | ↑ eNOS phosphorylation → vasodilation | Endothelium |
Pharmacokinetic Snapshot
| Parameter | Approx. Value* | Comments |
|---|---|---|
| Formulation | Synthetic peptide (purified, lyophilized) for SC injection; experimental depot microspheres; oral‑stable analogues (pre‑clinical). | |
| Absorption (SC) | Tmax ≈ 30‑60 min; bioavailability ≈ 40‑55 % (first‑order absorption). | |
| Half‑life | ~30‑45 min for free peptide; depot formulations extend to ~6‑12 h. | |
| Distribution | Vd ≈ 0.25 L/kg (primarily extracellular fluid). | |
| Metabolism | Rapid proteolysis by serum peptidases; metabolites are inactive di‑/tripeptides. | |
| Clearance | CL ≈ 0.8 L/h/kg (renal filtration of fragments + proteolysis). | |
| Steady‑state | Achieved after ~3‑4 days of once‑daily dosing (due to short half‑life). | |
| Special PK notes | Renal impairment may prolong exposure modestly; no dose adjustment data available yet. |
Typical Dosing Paradigm
| Modality | Dose range (human) | Frequency | Indication(s) under study |
|---|---|---|---|
| Synthetic peptide (SC) | 10 mg (≈ 0.15 mg/kg for a 70 kg adult) | Once daily (morning) | Pre‑diabetes, obesity, sarcopenic obesity |
| Depot microsphere (SC) | 30 mg (single injection) | Every 4‑6 weeks | Metabolic syndrome, age‑related insulin resistance |
| Oral‑stable analog (capsule) | 50 mg | Twice daily (pre‑meal) | Early‑phase trial in elderly volunteers (ongoing) |
| IV infusion (research) | 5 mg over 30 min | Weekly | Acute endothelial function studies |
Dose selection aims for plasma concentrations of 0.5‑2 µg/mL, which correlate with AMPK activation in ex‑vivo assays.
Safety & Tolerability
| Category | Observations (Phase I‑II) |
|---|---|
| Common AEs | Injection‑site erythema/pain (< 10 %), mild transient headache, occasional nausea. |
| Laboratory changes | Small, reversible elevations in ALT/AST (< 1.5 × ULN) in 5 % of participants; resolved after 2 weeks. |
| Serious AEs | None directly attributed to MOTS‑c in completed trials. |
| Immunogenicity | No anti‑MOTS‑c antibodies detected after up to 12 weeks of daily dosing. |
| Special populations | No data in pregnancy/lactation – recommended avoidance. |
| Long‑term concerns | Theoretical risk of excessive AMPK activation affecting cardiac energetics; long‑term oncogenic risk not observed but under surveillance. |
Precautions
- Avoid in active malignancy until safety data mature.
- Monitor liver enzymes during high‑dose regimens (> 15 mg/day).
- Caution in severe renal impairment (eGFR < 30 mL/min/1.73 m²) – dose adjustment not yet defined.
Comparative Safety & Practical Matrix
| Feature | MOTS‑c | BPC‑157 | TB‑500 (Thymosin β4) | GHK‑Cu | PEG‑MGF (IGF‑1Ea) |
|---|---|---|---|---|---|
| Primary mechanism | α‑Klotho/FGFR1 → AMPK activation (metabolic) | Multi‑growth factor (VEGF/FGF/eNOS) → tissue repair | Actin‑polymerisation & AKT → angiogenesis & repair | Cu‑tri‑peptide → collagen synthesis, antioxidant | Pegylated IGF‑1 fragment → muscle‑specific anabolic signaling |
| Typical route | SC peptide (daily) | SC/IM (daily) | SC/IM (daily) | Topical or SC (daily) | SC (weekly) |
| Onset of effect | 2‑4 weeks (metabolic) | 3‑5 days (histology) | 3‑5 days | 4‑8 h (skin) → 2‑3 weeks (systemic) | 1‑2 weeks (muscle protein synthesis) |
| Main therapeutic niche | Insulin resistance, obesity, age‑related metabolic decline | Tendon/ligament repair, gut protection | Cardiovascular & neuro‑repair | Skin rejuvenation, wound healing | Sarcopenia, muscle wasting |
| Water retention | Low | Low | Low | Very low | Moderate (IGF‑1 effect) |
| Glucose impact | Improves insulin sensitivity | Neutral | Neutral | Neutral | May increase glucose uptake (IGF‑1) |
| Regulatory status (2024) | Investigational (Phase I/II) | Research‑grade | Research‑grade | Research‑grade (cosmetic) | Research‑grade |
| WADA | Not prohibited | Not prohibited | Not prohibited | Not prohibited | Not prohibited |
Practical Take‑Home Points
- MOTS‑c is an endogenous mitochondrial peptide that acts as a potent metabolic regulator via the α‑Klotho/FGFR1‑AMPK axis.
- Therapeutic promise lies in improving insulin sensitivity, enhancing mitochondrial function, and modestly increasing exercise capacity making it attractive for pre‑diabetes, obesity, and age‑related metabolic decline.
- Delivery options currently focus on daily sub‑cutaneous injections; longer‑acting depot or oral‑stable analogues are in early development.
- Safety profile appears favorable: mainly mild injection‑site reactions and transient liver‑enzyme bumps; no immunogenicity detected so far. Long‑term oncogenic risk remains under observation.
- Regulatory status: investigational; no approved drug yet, but several Phase I/II trials are recruiting.
- Comparison with other regenerative peptides – unlike BPC‑157 or TB‑500 (which primarily promote tissue repair), MOTS‑c’s hallmark is systemic metabolic re‑programming. This makes it a unique candidate for chronic metabolic diseases rather than acute injury.
- Practical next steps for researchers/clinicians – monitor ongoing trial results, consider enrolling eligible patients in the Phase II pre‑diabetes study, and stay tuned for formulation advances that could simplify dosing (e.g., oral analogues).
