MOTS-c
MOTS-c is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the mitochondrial 12S rRNA gene that activates AMPK signaling to regulate glucose and lipid metabolism; it is studied preclinically as an exercise-mimetic and metabolic regulator, with no completed human clinical trials of exogenous administration.
MOTS-c reconstitution calculator
Open full calculator →Typical dosing
| Goal | Range | Route | Frequency |
|---|---|---|---|
| Human clinical dosing | None established | n/a | No completed human trial of exogenous MOTS-c — no validated dose, route or schedule exists |
| Rodent metabolic and physical-performance studies (Reynolds et al., Nat Commun 2021) | 5 or 15 mg/kg/day | Intraperitoneal (mice) | Daily for ~2 weeks |
| Late-life intermittent regimen in aged mice (Reynolds et al. 2021) | 15 mg/kg | Intraperitoneal (mice) | 3x weekly, begun at ~23.5 months of age |
| Community protocol (no clinical trial basis) | ~5-10 mg | SubQ | varies (informal community regimens) |
| Why rodent doses do not transfer to people | mg/kg in mice is not mg/kg in humans | n/a | Interspecies scaling is not linear and no human pharmacokinetic data for MOTS-c exist |
Ranges compiled from research literature — not a prescription.
How it works
MOTS-c is a mitochondrial-derived peptide (MDP) discovered by Lee et al. (2015, Cell Metabolism), encoded within a short open reading frame inside the mitochondrial 12S rRNA gene rather than nuclear DNA — an unusual origin among signaling peptides. In that founding study, MOTS-c administration prevented diet-induced obesity and reversed age-dependent, high-fat-diet-induced insulin resistance in mice, establishing it as a mitochondrial-to-nuclear metabolic signal.
Mechanistically, MOTS-c is reported to inhibit the folate cycle and downstream de novo purine biosynthesis, causing intracellular accumulation of AICAR, an endogenous AMP-activated protein kinase (AMPK) activator. This AMPK engagement increases glucose uptake and GLUT4 expression in skeletal muscle without depleting cellular energy stores, and a follow-up study (Cell Metabolism, 2018) showed MOTS-c can translocate to the nucleus under metabolic stress to regulate antioxidant-response gene expression.
Subsequent rodent work has extended these findings toward an "exercise-mimetic" profile. Reynolds et al. (2021, Nature Communications) reported that exercise sharply increases skeletal-muscle and circulating MOTS-c, and that intermittent MOTS-c dosing in aged mice roughly doubled running capacity and improved measures of physical function; a related report described MOTS-c reducing myostatin signaling and protecting against palmitic-acid-induced muscle atrophy in cell cultures.
Honestly: essentially all efficacy data for MOTS-c come from rodent and cell-culture studies. Some human observational work exists — exercise was shown to raise endogenous MOTS-c levels in muscle biopsies and plasma, and plasma MOTS-c has correlated inversely with fasting insulin, HbA1c, and BMI in cohort studies — but there are no completed human clinical trials evaluating exogenous MOTS-c administration for safety, dosing, or efficacy. All dosing figures circulating online are informal and not derived from any trial.
Side effects & safety
- Preclinical-only compound: virtually all data are from rodent and cell-culture studies, not humans.
- No established human safety profile, toxicology data, or clinical dosing regimen exists.
- Reported "community" doses/routes are informal and not derived from any trial — use amounts and frequency are unverified.
- Not FDA-approved for any use and not evaluated as a drug or supplement; sourced from research/gray-market suppliers with variable purity and quality control.
- Unknown interactions with other medications, supplements, or existing metabolic/endocrine conditions.
- Anyone considering use should consult a licensed physician; this content is informational only and not medical advice.
Research
Primary sources — PubMed.
- Lee C, et al. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metab. 2015. https://www.sciencedirect.com/science/article/pii/S1550413115000613
- Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021. https://www.nature.com/articles/s41467-020-20790-0
- Kim KH, et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab. 2018. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30390-5
- MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation (review). PMC. 2023. https://pmc.ncbi.nlm.nih.gov/articles/PMC9905433/
- MOTS-c: an equal opportunity insulin sensitizer (review). PMC. 2019. https://pmc.ncbi.nlm.nih.gov/articles/PMC6462348/
- MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab / PMC. 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8238132/