MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) is the second mitochondrially encoded peptide after Humanin—a 16-amino-acid molecule encoded in mitochondrial 12S rRNA. Under normal conditions, MOTS-c is produced in skeletal muscle in response to exercise and appears in circulation—a true “exercise hormone” from the mitochondrial genome, not the nucleus. Plasma levels decline with age; in high-fat-diet mice they are further suppressed, correlating with loss of metabolic flexibility.
The central biochemical mechanism: MOTS-c targets the folate cycle in mitochondria, causing AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) accumulation—an allosteric AMPK activator. AMPK activation drives GLUT4 translocation in muscle, fatty acid β-oxidation, and via PGC-1α, mitochondrial biogenesis. Under metabolic stress, MOTS-c translocates to the nucleus and directly regulates nuclear genes of stress adaptation. In Nature Communications, MOTS-c in aged mice restored running endurance, muscle metabolism, and AMPK activation to young-animal levels—synergistically with actual training.
Systemic effects extend beyond muscle. In metabolic models: reduced insulin resistance, normalized hepatic lipids, and lower inflammatory markers. In longevity context: improved physical function in old mice independent of body weight—healthspan, not just lifespan. Human clinical data remain limited, but as the second MDP class member with a detailed molecular mechanism, MOTS-c holds a significant place in mitochondrial longevity pharmacology.
⚡ AMPK and mitochondrial biogenesis: ★★★★★
🏃 Physical endurance and muscle metabolism: ★★★★★
🍬 Insulin sensitivity and lipid metabolism: ★★★★☆
✅ Safety: ★★★★☆ (endogenous molecule; no adverse findings in studies)
⚠️ Possible sensations and side effects: neutral in preclinical data; limited human data
🤝 Combinations (goal → stack)
⚡ Mitochondrial protocol → MOTS-c + Humanin
🏃 Metabolism + exercise → MOTS-c + SLU-PP-332
🧬 Longevity + mitochondria → MOTS-c + NAD+
| CAS number | 1627580-64-6 |
| Batch purity | 99.45 % |
Full details in our guide
https://peptideboost.club/guide/mots-c
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