MOTS-c
A mitochondrial-encoded peptide that acts as an exercise mimetic - improving metabolic flexibility, insulin sensitivity, and longevity pathways.
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Compound Profile
MOTS-c
Key Data
Research reference only
Research Focus
Preclinical data
⚠ Research & Educational Use Only. MOTS-c is a research chemical documented here for scientific education. All information references peer-reviewed literature and preclinical/clinical study data. Not for human consumption. Not medical advice. Consult a licensed researcher or healthcare professional before any laboratory use.
- Mitochondria-encoded peptide (mitokine) - regulated by mitochondrial stress and exercise, acting as an endogenous exercise signal
- Acts as an exercise mimetic - activates AMPK and FOXO pathways that mediate exercise benefits without physical activity
- Dramatically improves insulin sensitivity - reverses diet-induced insulin resistance in animal models
- MOTS-c is not FDA-approved for human use. It is a research chemical for scientific study only.
Research At a Glance
- Mitochondria-encoded peptide (mitokine) - regulated by mitochondrial stress and exercise, acting as an endogenous exercise signal
- Acts as an exercise mimetic - activates AMPK and FOXO pathways that mediate exercise benefits without physical activity
- Dramatically improves insulin sensitivity - reverses diet-induced insulin resistance in animal models
- Reduces adiposity selectively, particularly visceral fat, without affecting lean mass
In Plain English
Simple summaryMOTS-c is a 16-amino acid peptide encoded not in the cell's nuclear DNA but in the mitochondrial genome -- specifically in the 12S rRNA region. That's what makes it genuinely unusual: it's one of a very small class of mitochondria-derived peptides (MDPs) that can leave the mitochondria, enter the bloodstream, and act as a signaling molecule throughout the body. It was discovered by Changhan David Lee's lab at USC in 2015. The initial research showed it activated AMPK -- the cellular energy sensor that's also activated by exercise and calorie restriction -- and produced meaningful improvements in insulin sensitivity, fat metabolism, and exercise capacity in mouse models. More recent work has shown MOTS-c levels decline with age, and that supplementing aged mice restores aspects of youthful metabolic function.
- Mitochondria-encoded peptide (mitokine) - regulated by mitochondrial stress and exercise, acting as an endogenous exercise signal
- Acts as an exercise mimetic - activates AMPK and FOXO pathways that mediate exercise benefits without physical activity
- Dramatically improves insulin sensitivity - reverses diet-induced insulin resistance in animal models
The full scientific detail, mechanisms, citations, and dosing data, follows below.
What is MOTS-c?
Tap any underlined term for an instant definition.
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino acid mitochondria-derived peptide (MDP) encoded within the 12S rRNA gene of mitochondrial DNA. It regulates metabolic homeostasis, promotes exercise-like metabolic effects, and its circulating levels decline with age.
What It Is
- A 16-amino acid peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg) encoded by a small ORF within the 12S rRNA of human mitochondrial DNA
- Part of the growing family of mitochondria-derived peptides (MDPs) alongside Humanin and SHLPs
- Circulating levels decline with age and in metabolic disease; exercise acutely increases MOTS-c levels in muscle and plasma
- Acts as an exercise mimetic by activating AMPK and the folate cycle (one-carbon metabolism) in skeletal muscle
How It Works
- AMPK activation: translocates to the nucleus under cellular stress and activates AMPK through folate cycle disruption (inhibits 5-aminoimidazole-4-carboxamide ribonucleotide; this raises AMP-to-ATP ratio)
- Folate-AICAR axis: in skeletal muscle cells, MOTS-c increases AICAR levels by competing with folate pathway intermediates; AICAR then activates AMPK; example: MOTS-c-treated myotubes showed 3-fold increase in AMPK phosphorylation and 2-fold increase in GLUT4 expression vs untreated
- Promotes glucose uptake: GLUT4 translocation independent of insulin via AMPK
- Reduces lipid accumulation: inhibits lipogenesis genes in liver and adipose tissue
- Anti-inflammatory: reduces NF-kB activation; lowers TNF-alpha and IL-6 in metabolic inflammation models
Key Research Findings
- Exercise mimetic: intraperitoneal MOTS-c (5 mg/kg) for 4 weeks in mice on high-fat diet prevented obesity, improved insulin sensitivity, reduced fat accumulation; sedentary mice treated with MOTS-c performed comparably to exercise-trained controls in metabolic tests
- Insulin resistance reversal: MOTS-c restored insulin sensitivity in high-fat diet-induced obese mice (insulin tolerance test AUC normalised); liver steatosis (oil red O staining) reduced by 60%
- Age-related metabolic decline: exogenous MOTS-c in 10-month-old mice restored exercise capacity and metabolic flexibility to 3-month-old levels
- Exercise boost: MOTS-c injected before treadmill exercise increased running endurance by 20-30% compared to exercise alone in mouse models; suggests additive effect with actual physical activity
Dosing From the Literature
- Mouse studies: 5-15 mg/kg/day subcutaneous or intraperitoneal
- Research protocols (human-applicable extrapolation): 5-25 mg subcutaneous daily or 3-4 times weekly
- No established human clinical dose; early Phase 1 safety data under investigation
Storage and Handling
- Lyophilised: -20 degrees C; stable 24 months
- Reconstituted: 2-8 degrees C; use within 7 days
- MOTS-c is relatively small and stable; less prone to degradation than larger peptides
By the Numbers
Key Research Benefits
Documented effects observed in preclinical and clinical studies on MOTS-c. See all Metabolic & Weight peptides for comparison.
Side Effects & Risks
Adverse effects reported in the research literature. All data sourced from preclinical and clinical study reports. View all peptides' side effects →
Dosing Data from the Literature
Doses referenced below are sourced from published preclinical and clinical studies. Use the peptide dose calculator to convert these values to injection volume.
MOTS-c research dosing is based primarily on animal studies. Rodent protocols use 5–15 mg/kg subcutaneously. Research community protocols for humans have explored 10–15 mg subcutaneously daily or every other day.
Conservative starting protocol: 5 mg every other day for 2 weeks, then increase to daily dosing based on tolerance. Typical cycle: 4–8 weeks on with 4-week breaks.
Exercise timing: some researchers administer MOTS-c 30–60 minutes before training to maximise the exercise mimetic effects - combining the compound's metabolic activation with the additional stimulus of actual exercise for potentially synergistic metabolic improvement.
Administration in Research Settings
Standard reconstitution and administration methodology for laboratory research use.
Reconstitute MOTS-c with bacteriostatic water. For a 10 mg vial: 1 ml BAC water gives 10 mg/ml; a 5 mg dose is 0.5 ml. Administer subcutaneously via insulin syringe. Monitor blood glucose before and after the first several injections due to MOTS-c's insulin-sensitising effects.
Timing: morning administration aligns with the circadian pattern of metabolic signalling and is the most common protocol. Pre-workout administration is used by some researchers to amplify the metabolic effects of exercise.
Store at -20°C (lyophilised). Reconstituted: 2–8°C for 21 days.
What the research doesn't show
All the impressive MOTS-c data -- weight loss, insulin sensitivity, exercise enhancement -- comes from mouse models. Human clinical trials don't exist yet. The concept is scientifically credible (the mechanism is real, the decline with age is documented in humans), but translating rodent metabolic results to humans has a poor track record. This is a promising but early-stage research area.
Research Video
Medical Expert Videos
Physicians, researchers, and pharmacologists explain MOTS-c, covering mechanisms of action, clinical context, and study findings.
Videos sourced from YouTube search. KnowYourPeptide does not endorse any individual creator. For research education only.
The Bottom Line
MOTS-c has a growing body of preclinical evidence and a well-characterised safety profile in research settings. The most-studied application is: mitochondria-encoded peptide (mitokine) - regulated by mitochondrial stress and exercise, acting as an endogenous exercise signal.
The most commonly reported side effect in research subjects is limited human data - most research in rodent models. It is a research chemical, not approved for human use.
Frequently Asked Questions
Explore Further
Quick Reference
Research Articles
- Epithalon vs MOTS-c: Comparing Longevity Peptide Research7 min read
- SS-31 (Elamipretide): Mitochondrial Research in Aging Models8 min read
How It Compares
Humanin is the other well-known mitochondria-derived peptide and comes from the same mitochondrial genome region. Humanin is primarily studied for neuroprotection; MOTS-c is primarily metabolic. They're complementary rather than redundant. AICAR is a synthetic AMPK activator that works through a similar downstream pathway but is not a peptide and has a different safety profile.
Compare MOTS-c side-by-sideResearch Use Only
This information is for educational research purposes only. This is not medical advice. Consult a qualified healthcare professional.