Educational reference, not medical advice. This page summarizes information from published research and regulatory filings for educational purposes. It is not a recommendation to use any compound and should not replace guidance from a licensed healthcare provider. Most peptides discussed here are not approved for the uses described.
What it is
MOTS-c — "Mitochondrial ORF of the 12S rRNA-c" — is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene. Like humanin (encoded in the 16S rRNA), it is a "small open reading frame" peptide from the mitochondrial genome that the Cohen lab identified by combining computational ORF prediction with experimental characterization.
The peptide is produced in mitochondria, exported to the cytoplasm, and detectable in human plasma at low nanomolar concentrations. Circulating levels appear to rise with exercise and decline with age, observations that have driven much of the subsequent interest in MOTS-c as a metabolic regulator.
History
The discovery paper from Changhan Lee and colleagues in Pinchas Cohen's group at USC was published in Cell Metabolism in 2015. The paper described MOTS-c as a regulator of insulin sensitivity, energy metabolism, and weight gain in mice — with peripheral administration producing improvements in glucose tolerance, reduced diet-induced obesity, and increased running endurance.
Subsequent work from multiple groups has reported convergent findings: AMPK activation as a downstream effect, exercise-like adaptations in skeletal muscle, cardioprotection in diabetic models, and modulation of bone and immune cell biology. Published research now spans roughly 250 papers across the decade since discovery.
Despite the volume of preclinical work, MOTS-c has not entered formal drug development. The Cohen group founded the spinout CohBar to develop mitochondrial peptides, which pursued related analogs (notably CB4209 / CB4211 for NASH) rather than MOTS-c directly. CohBar wound down in 2023.
Regulatory status
Not approved by any regulator. No registered human clinical trial of exogenous MOTS-c as a therapeutic agent is active as of 2026. Not on the FDA 503A compounding list. Sold through research peptide channels with not-for-human-use labeling.
How researchers describe its action
Mechanism papers describe MOTS-c entering target tissues, translocating to the nucleus under metabolic stress, and modulating gene expression in coordination with the AMPK signaling pathway. Reported downstream effects include increased glucose uptake in skeletal muscle (largely insulin-independent), suppression of hepatic gluconeogenesis, improved mitochondrial biogenesis, and shifts in immune cell phenotype.
The most reproducible finding across labs is that MOTS-c administration mimics aspects of the exercise response — particularly AMPK activation and PGC-1α induction — which has driven its popular framing as an "exercise mimetic." Whether the same effects occur in humans at achievable subcutaneous doses has not been tested in a controlled trial.
Half-life and dosing intervals
Published rodent pharmacokinetic data suggests a circulating half-life on the order of 1 to 2 hours after subcutaneous administration, with relatively broad tissue distribution. This is longer than humanin but still short compared with engineered peptides like the GLP-1 agonists.
In rodent studies, common doses are in the range of 0.5 to 5 mg per kilogram daily, given intraperitoneally or subcutaneously. Human doses described in observational use online — typically 5 to 10 mg per day subcutaneously, often cycled — are extrapolated from the rodent data without confirmed human pharmacokinetics.
Reconstitution example
MOTS-c is supplied lyophilized in small vials, typically 5 mg or 10 mg. A 10 mg vial reconstituted with 2 mL of bacteriostatic water yields 5 mg/mL. On a 1 mL U-100 insulin syringe, 20 units (0.2 mL) delivers 1 mg, and 50 units (0.5 mL) delivers 2.5 mg. Vial's calculator handles the conversion when vial mass and water volume are entered.
What to know
- Preclinical only. All efficacy evidence is in cultured cells, rodents, or human observational data showing circulating MOTS-c declines with age. No interventional human trial has been published.
- Exercise-mimetic framing. The preclinical phenotype overlaps meaningfully with exercise adaptation in skeletal muscle. The framing as an "exercise in a vial" outpaces what controlled human data supports.
- Not approved, not compoundable. No regulator has authorized MOTS-c for any use. Compounding pharmacies in the United States cannot legally prepare it.
- Storage. Lyophilized: refrigerate, protect from light. Reconstituted: refrigerate and use within 2 to 4 weeks per typical short-peptide stability data.
- Safety profile is incomplete. No long-term human safety data. User reports describe injection-site irritation; rare effects are uncharacterized.
Sources
- 1.Lee C et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism.
- 2.Yoon TK et al. (2022). Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c). Diabetes & Metabolism Journal.
- 3.Yang B et al. (2021). MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression. Biochimica et Biophysica Acta - Molecular Basis of Disease.
- 4.Li S et al. (2022). MOTS-c and Exercise Restore Cardiac Function by Activating NRG1-ErbB Signaling in Diabetic Rats. Frontiers in Endocrinology.