Compound reference
MOTS-c
Also known as Mitochondrial Open Reading Frame of the 12S rRNA-c
MOTS-c is a peptide encoded within mitochondrial DNA that acts as an exercise mimetic and metabolic regulator. Its preclinical data (insulin sensitivity, aging, exercise capacity) are strong and a Phase 2a trial is underway — but no completed human efficacy trial exists, and it is banned in sport as an AMPK activator.
- CAS
- 1627580-64-6
- Formula
- C₁₀₁H₁₅₂N₂₈O₂₂S₂
- Molar mass
- ≈2174.6 g/mol
- Sequence
- MRWQEMGYIFYPRKLR — 16 residues, encoded within the mitochondrial 12S rRNA gene
- Half-life
- short (minutes); effects attributed to downstream signaling
Research peptide; not FDA-approved as a drug.
Mode of action
MOTS-c is one of biology's more surprising molecules: a 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded not in the cell nucleus but within the mitochondrial genome, in the 12S rRNA gene — a "mitochondrial-derived peptide" (MDP). It functions as a metabolic regulator and a mediator of mitochondrial-to-nuclear communication. Mechanistically it activates the cellular energy sensor AMPK, and under metabolic stress it translocates to the nucleus, where it influences the expression of antioxidant and metabolic genes (including the NRF2/antioxidant-response program). More recent work shows it directly binds and activates the kinase CK2 in skeletal muscle. Functionally the through-line is insulin sensitization and an "exercise-mimetic" effect — and indeed MOTS-c is itself released into the circulation by exercising muscle.
Main intended effect
To improve metabolic health and physical capacity — enhancing insulin sensitivity, energy metabolism, and exercise/aging-related muscle function.
Areas of interest
The core interest is metabolic: obesity, insulin resistance and type 2 diabetes, fatty liver, and the biology of exercise and aging (MOTS-c declines with age and rises with exercise). Secondary strands include bone metabolism, cardiac protection in diabetes, and cognitive/neurological relevance. In the consumer market it is sold as a metabolic, fat-loss, and "exercise-in-a-vial" longevity peptide.
Evidence for intended effects
The preclinical evidence is genuinely strong and mechanistically coherent. The discovery study showed MOTS-c promotes metabolic homeostasis and reduces diet-induced obesity and insulin resistance in mice. A landmark follow-up established MOTS-c as an exercise-induced peptide that improves running capacity and physical function in aged mice — and confirmed its release during exercise in humans. Further work has detailed its CK2 mechanism and benefits in diabetic cardiomyopathy models.
The human evidence, however, is not yet there. There is no completed randomized efficacy trial of MOTS-c itself in people. The closest completed human data come from CB4211, a MOTS-c analogue (CohBar), which finished a Phase 1a/1b study in NAFLD and obesity; a Phase 2a trial of MOTS-c itself for insulin sensitivity in prediabetes is registered and underway. So MOTS-c sits at an interesting inflection: compelling biology and emerging clinical testing, but unproven in humans as of now.
| Strand | What exists | Tier |
|---|---|---|
| Metabolic (obesity, insulin) | Discovery + multiple mouse studies | Strong preclinical |
| Exercise / aging | Exercise-induced; improves aged-mouse capacity; human release confirmed | Strong preclinical |
| Human efficacy | CB4211 analogue Phase 1; MOTS-c Phase 2a registered/underway | Early / none completed |
| Mechanism | AMPK, nuclear translocation, CK2 binding | Well characterized |
Studied amounts (literature dosing context)
Animal studies dosed MOTS-c intraperitoneally (for example 5–15 mg/kg in the exercise-capacity work; 0.5 mg/kg/day in a diabetic-cardiomyopathy model). The registered human Phase 2a trial uses investigational subcutaneous MOTS-c. These are preclinical and trial figures; there is no established human dose, and this page does not provide dosing guidance.
Safety and regulatory status
MOTS-c is not an FDA-approved drug. The FDA has placed it in the Category 2 list of bulk substances that may present significant safety risks for compounding, citing immunogenicity and characterization concerns. Importantly for athletes, MOTS-c is explicitly prohibited by the World Anti-Doping Agency (2026 Prohibited List) as an AMPK-activating metabolic modulator, and anti-doping agencies have published explainers on it. Material sold as research-grade "MOTS-c" is unregulated and of unverified identity and purity. It belongs to the mitochondrial-derived-peptide family alongside humanin, and is often grouped with the (mechanistically different) mitochondrial protectant SS-31.
Sources
The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance
The original MOTS-c discovery paper (Lee and colleagues) identifying a 16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA gene. Using C57BL/6 and CD-1 mice on a 60%-fat diet, the investigators administered MOTS-c intraperitoneally at 5 mg/kg/day for 7 days or 0.5 mg/kg/day for 8 weeks and treated L6 rat myotubes and HeLa cells at 10 µM. MOTS-c inhibited the folate cycle and de novo purine biosynthesis, causing AICAR accumulation and downstream AMPK activation (elevated Thr172 phosphorylation) in skeletal muscle. Treated obese mice showed prevention of age- and diet-induced insulin resistance with improved glucose infusion rate, reduced body weight, and lower plasma insulin. All evidence is from cell culture and mouse models; human pharmacokinetics and therapeutic dosing remain unestablished.
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds and colleagues demonstrated that MOTS-c is released into circulation by exercising skeletal muscle in 10 young male human volunteers and in C57BL/6J and C57BL/6N mice. Intraperitoneal MOTS-c at 5 or 15 mg/kg improved treadmill running time in young mice (p = 0.0069 for 15 mg/kg vs. 0 mg/kg) and dramatically increased physical capacity in old mice (p = 0.000002 vs. old controls). Intermittent dosing (3× per week) in aged mice also improved grip strength (p = 0.000078), stride length (p = 0.0038), fat mass (p < 1×10⁻⁵⁰), and blood glucose. The mechanism involves MOTS-c regulating nuclear genes linked to metabolism and proteostasis in aged skeletal muscle, with HSF1 implicated in myoblast stress survival. All in vivo efficacy data are from mouse models; human interventional evidence is absent.
MOTS-c modulates skeletal muscle function by directly binding and activating CK2
Mechanistic study (Kumagai and colleagues) combining cell-free CK2 biochemistry, differentiated skeletal muscle and adipocyte cell lines, young (2 months) and aged (22 months) mice, high-fat-diet-fed mice, and genetic data from 1,241 Japanese individuals to establish that MOTS-c directly binds and activates casein kinase 2 (CK2) in skeletal muscle. In mice, 8-week MOTS-c administration at 5 mg/kg/day IP significantly increased skeletal muscle CK2 activity (p < 0.01) and enhanced muscle glucose uptake; CK2 inhibition with CX-4945 blunted these effects. MOTS-c's action was tissue-specific — activating CK2 in muscle while suppressing it in adipose tissue despite systemic delivery. The naturally occurring K14Q variant showed reduced CK2 binding affinity and blunted functional activity, and K14Q human carriers displayed higher risk of sarcopenia and type 2 diabetes in an age- and activity-dependent manner (p < 0.05). Findings are in mouse models and a single Japanese cohort; generalizability across populations and clinical translation require further study.
MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats
Diabetic cardiomyopathy study in male Sprague-Dawley rats (n = 40) in which type 2 diabetes was induced by a 7-week high-fat diet followed by streptozotocin (30 mg/kg), and MOTS-c was administered at 0.5 mg/kg/day IP for 8 weeks post-induction. MOTS-c significantly reduced fasting glucose (p < 0.01) and HOMA-IR (p < 0.05) versus untreated diabetic controls, restored ejection fraction to control levels (p < 0.01), normalized E/A ratio and left-ventricular posterior-wall diastolic thickness, and recovered citrate synthase activity as a marker of mitochondrial function. At the molecular level, qRT-PCR and Western blot showed significant downregulation of CCN1, ERK1/2 phosphorylation, and EGR1 mRNA and protein (p < 0.01–0.05), with concurrent PGC-1α protein upregulation (p < 0.01). The proposed mechanism is suppression of myocardial apoptosis through CCN1/ERK1/2/EGR1 pathway inhibition and mitochondrial structure restoration. All findings are from male rats at a single dose; sex-specific effects and human cardioprotection remain to be evaluated in clinical settings.
MOTS-c — Cognitive Vitality Report
Evidence summary produced by the Alzheimer's Drug Discovery Foundation (Cognitive Vitality series, 2025) evaluating the mitochondria-derived peptide MOTS-c (sequence MRWQEMGYIFYPRKLR) for cognitive and neurological relevance. The report documents the peptide's molecular characteristics, notes that no therapeutic dose has been established in humans, and identifies blood-brain-barrier non-penetrance as a key limitation for CNS applications. Preclinical metabolic dosing data and the clinical analogue CB4211 (NCT03998514) are discussed to contextualise translational development status. The ADDF concludes that therapeutic safety and effective dosing for MOTS-c remain unestablished, and characterises the compound as being at an early investigational stage with no approved human indication. The report is an evidence-grading exercise rather than a primary study, and conclusions reflect the state of the literature at time of publication.
https://www.alzdiscovery.org/uploads/cognitive_vitality_media/MOTS-c.pdf
A Phase 1a/1b Study of Safety, Tolerability, and Pharmacokinetics of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease
ClinicalTrials.gov registry record (NCT03998514) for a completed Phase 1a/1b, three-part, randomized, double-blind, placebo-controlled study of CB4211, a MOTS-c analogue developed by CohBar, enrolling 88 participants. Part A evaluated single ascending doses in healthy non-obese volunteers, Part B assessed multiple ascending doses over 7 days, and Part C administered 28-day dosing in subjects with nonalcoholic fatty liver disease. Primary outcomes were incidence and severity of adverse events, laboratory abnormalities, vital signs, ECG changes, and injection-site reactions. No results have been posted to the registry. This record provides the human safety and pharmacokinetic exposure context for a MOTS-c analogue rather than for native MOTS-c itself.
A Phase 2a, Randomized, Double-blind, Placebo-controlled Study of MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity
Registered Phase 2a, randomized, double-blind, placebo-controlled trial (NCT07505745) evaluating whether 12 weeks of investigational subcutaneous MOTS-c improves insulin sensitivity, measured by the Matsuda index from an oral glucose tolerance test, versus placebo in adults with prediabetes and overweight or obesity who also receive standardized lifestyle counseling; safety follow-up extends to week 16. This represents the key registered human efficacy study of native MOTS-c peptide administration, building on preclinical evidence of mitochondrial-derived peptide regulation of glucose metabolism. As of April 2026, the trial is registered and enrolling; no efficacy or safety results have been posted, so clinical benefit in humans remains unestablished.
WADA Prohibited List 2026 — MOTS-c as an AMPK Activator (S4.4.1)
The World Anti-Doping Agency (WADA) 2026 Prohibited List, approved September 2025 and in force from 1 January 2026, explicitly names MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) as a prohibited substance. MOTS-c is listed under class S4 (Metabolic Modulators), sub-section 4.4.1, which covers Activators of the AMP-activated protein kinase (AMPK). Class S4 substances are prohibited at all times — both in-competition and out-of-competition — and are classified as non-specified substances, carrying a presumptive four-year sanction for a first anti-doping rule violation. No therapeutic use exemption is available because MOTS-c has no approved therapeutic indication in any jurisdiction. This prohibition reflects WADA's position that AMPK activators confer performance advantages through modulation of cellular energy metabolism.
MOTS-c Bulk Drug Substance for Compounding (FDA)
FDA bulk-substances compounding record classifying MOTS-c in the Category 2 list of substances that may present significant safety risks under the 503A compounding framework. The agency's stated concerns encompass possible immunogenicity risk depending on route of administration, complexities in identifying and controlling peptide-related impurities, and difficulties in adequately characterizing the active ingredient. Critically, FDA reported it had not identified human exposure data for any MOTS-c-containing compounded product by any route of administration, leaving the safety profile in humans largely unknown. As a Category 2 substance, MOTS-c cannot be used by 503A compounding pharmacies pending further regulatory evaluation. This classification is distinct from, but consistent with, MOTS-c's status as a prohibited substance in sport under WADA.