MOTS-c is a mitochondrial-derived peptide that regulates energy metabolism, enhances insulin sensitivity, supports mitochondrial biogenesis, and protects against oxidative stress. It can mimic exercise-like benefits and may improve obesity, diabetes, age-related decline, and endurance by activating energy pathways (e.g., AMPK).
MOTS-c
Also known as: Mitochondrial Open Reading Frame of the 12S rRNA-c
Overview
Benefits
- Weight loss support
- Diabetes management (insulin sensitivity)
- Anti-aging effects
- Exercise performance
- Cardiovascular support
- Bone health
Consider This Peptide If You Want To
- Enhance mitochondrial function and energy production
- Improve insulin sensitivity and longevity markers
Dosage & Administration
Dosage Guidelines
Recommended Dosage
• Amount:2.5 mg
• Frequency:thrice weekly
• Duration:6 weeks
• Rest Period:6 weeks
• Time of Day:morning
• Ingestion:subcutaneous
Administration Routes:Subcutaneous
Research Findings on Dosage:
• Subcutaneous Injection:
◦ Commonly Reported Dosage: 2.5-5 mg three times per week (M/W/F)
◦ Duration: 4-6 week cycle with 4-6 week break
▪ Reduce to 5 mg once per week for an additional 4 weeks
◦ Administration Notes:
▪ Some individuals receive optimal results with ½ dosage (2.5 mg)
▪ Individuals who are already mitochondrially optimized may experience an energy boost
Mechanism of Action
Mechanism of Action
How this peptide works in the body
AMPK Activation:
MOTS-c activates AMP-activated protein kinase (AMPK) by increasing intracellular 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), a direct AMPK agonist. This enhances fatty acid oxidation and glycolysiswhile inhibiting lipogenesis and gluconeogenesis, shifting metabolism toward ATP production. By promoting ACC (acetyl-CoA carboxylase) phosphorylation, MOTS-c improves energy efficiency under metabolic stress.
Glucose Metabolism:
MOTS-c enhances glucose uptake by upregulating GLUT4 (glucose transporter type 4) translocation via the insulin-independent AMPK pathway. It also influences PI3K-Akt signaling, improving glucose metabolism independently of insulin, which benefits insulin-resistant states like type 2 diabetes.
Mitochondrial Biogenesis:
MOTS-c promotes mitochondrial replication through PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and NRF1 (nuclear respiratory factor 1) activation. By increasing TFAM (mitochondrial transcription factor A) expression, it enhances mitochondrial DNA replication and oxidative phosphorylation, boosting ATP production and adaptability to metabolic stress.
Folate Cycle Modulation:
MOTS-c suppresses the methionine-folate pathway by interacting with 5-methyltetrahydrofolate (5-MTHF) and methionine synthase (MTR), reducing methionine conversion. This preserves NAD+ (nicotinamide adenine dinucleotide) levels, supporting sirtuin activation (SIRT1/SIRT3) for improved mitochondrial function, energy production, and oxidative stress resistance.
Consider Stacking With
- Any GHRP (Ipamorelin, Hexarelin)
- Any GHRH (CJC-1295, MOD-GRF-1295, Tesamorelin)
- Semaglutide/Tirzepatide
- AOD-9604
- Humanin
- ARA-290
- SS-31
- Kisspeptin-10
- 5-Amino-1MQ
Side Effects & Cautions
Common Side Effects
- Injection site redness/itchiness/swelling
- Water retention
- Mild fatigue on initiation
Cautions
- Start low (e.g., 2.5 mg) to assess response
- Hydrate; consider morning/pre-workout timing
Rare Side Effects
- Possible drop in blood sugar
- Rare flu-like symptoms
Research & References
Research Highlights
Metabolic Regulation: Demonstrated increased glucose uptake and reduced fat accumulation in high-fat diet-fed mice.
Anti-Obesity Effects: Shown to activate thermogenesis in brown adipose tissue and enhance "browning" of white fat.
Osteoporosis: Improved bone density and collagen synthesis in rodent models of menopause-induced osteoporosis.
Exercise and Performance: Enhanced AMPK activation and GLUT4 levels in skeletal muscle, improving endurance and metabolic flexibility.
References
Lee C, Kim KH, Cohen P. "MOTS-c: A mitochondrial-derived peptide regulating muscle and fat metabolism." J Physiol. 2016;595(21):6613-6621
Lu H et al. "MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction." Cell Metab. 2019;29(6):1249-1262
Yang Y et al. "The role of mitochondria-derived peptides in cardiovascular disease." J Cell Physiol. 2019;234(12):23407-23419
Che N et al. "MOTS-c and osteoporosis: Regulation via TGF-Beta/SMAD pathway." J Bone Miner Res. 2019;34(3):557-564