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Research in plain language

MOTS-c

MOTS-c

What it is

MOTS-c is a 16-amino-acid peptide encoded inside the mitochondrial 12S rRNA gene. In animal studies it activates the cellular energy sensor AMPK and is studied mainly for improving insulin sensitivity, reversing diet- and age-related metabolic decline, and boosting exercise/running capacity. In humans it is mostly studied as a naturally circulating peptide that rises with exercise, not yet as an administered drug.

Dosing Reference from Studies

Mixed (human and animal)Preclinical animal dose (per body weight)

0.5 mg/kg/day to 15 mg/kg

Dose in studies

Discussed in research communities 5-10 mg/week (SC)

Reference from peptide forums and community discussions. Not a recommendation, not based on studies, and not an established human protocol.

No established human protocol

Dosing Reference from StudiesCalculate syringe volume ->

How studies used it

Model
Mouse (C57BL/6, young and aged; also high-fat-diet fed)
Studied for
Diet-induced obesity and insulin resistance (metabolic)
Dose
5 mg/kg/day for the short glucose/insulin-sensitivity experiments; 0.5 mg/kg/day for the 8-week obesity-prevention experiment
Dosing
Once daily
Route
Intraperitoneal
Duration
7 days (insulin-sensitivity arm) and 8 weeks (high-fat-diet obesity-prevention arm)

Effects measured: MOTS-c improved glucose tolerance and insulin sensitivity in glucose-tolerance and hyperinsulinemic-euglycemic clamp tests. In the 8-week high-fat-diet arm at 0.5 mg/kg/day, treated mice were protected against diet-induced obesity (lower body weight gain) and against high-fat-diet-induced insulin resistance and hyperinsulinemia. Mechanistically the peptide acted largely in skeletal muscle, inhibiting the folate-purine cycle and activating AMPK.

Side effects: No adverse events reported in this study

Sources: Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015.

Model
Mouse (male C57BL/6J, ~17 weeks, high-fat diet since 5 weeks of age)
Studied for
High-fat-diet insulin resistance and plasma metabolite profile (metabolic)
Dose
2.5 mg/kg per dose
Dosing
Twice daily
Route
Intraperitoneal
Duration
3 consecutive days

Effects measured: Treated mice showed a significant reduction in blood glucose versus controls, and insulin and leptin trended lower. Untargeted metabolomics showed MOTS-c reduced plasma metabolites in sphingolipid, monoacylglycerol and dicarboxylate pathways, consistent with improved insulin sensitivity. Effects were seen after only 3 days.

Side effects: No adverse events reported in this study

Sources: Kim SJ, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological Reports. 2019.

Model
Mouse (C57BL/6 at 2, 12 and 22 months; plus very old >30 months for the late-life arm)
Studied for
Age-dependent physical decline and exercise capacity (exercise/metabolic)
Dose
5 mg/kg/day and 15 mg/kg/day
Dosing
Once daily for the acute treadmill arms; intermittent 3 times per week for the late-life arm
Route
Intraperitoneal
Duration
About 2 weeks for the acute treadmill arms; ongoing from ~23.5 months of age for the late-life longevity/healthspan arm

Effects measured: On the high dose (15 mg/kg/day), 100% of young treated mice reached the top sprint speed (23 m/min) versus 16.6% of controls. Old treated mice ran roughly 2-fold longer in time and about 2.16-fold farther in distance than controls. Late-life intermittent dosing (3x/week) in very old mice improved grip strength, stride length and 60-second walking capacity. The paper also reported that in humans acute exercise raised MOTS-c about 11.9-fold in skeletal muscle and roughly 1.5 to 1.6-fold in circulation (this human arm was observational, no peptide given).

Side effects: No adverse events reported in this study

Sources: Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021.

Model
Rat (female Sprague-Dawley, ~120 g) and mouse (female C57BL/6J, 10-11 weeks)
Studied for
Acute exercise/endurance performance (exercise capacity)
Dose
15 mg/kg
Dosing
Single dose given about 10 minutes before the exercise test
Route
Intraperitoneal
Duration
Single dose (acute test); chronic arm used 4-8 weeks of voluntary running, not peptide dosing

Effects measured: A single 15 mg/kg dose 10 minutes before testing increased total running time by about 12% and running distance by about 15% in untrained mice. No saline-injected mouse finished the 40-minute test, whereas 5 of 6 MOTS-c-treated mice did. Separately, 4-8 weeks of voluntary running (no peptide) raised endogenous skeletal-muscle MOTS-c protein 1.5 to 5-fold, with elevation persisting weeks into detraining.

Side effects: No adverse events reported in this study

Sources: Hyatt JK. MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiological Reports. 2022.

Model
Human, professional endurance athletes (75 athletes, 63 male/12 female) vs 30 sedentary age- and BMI-matched controls
Studied for
Association of habitual endurance exercise with circulating MOTS-c (exercise physiology, observational)
Dose
Not applicable: observational study, no MOTS-c was administered. Reported endogenous serum levels were about 2.36 ng/mL (low/moderate endurance) and 2.22 ng/mL (high endurance) versus 3.89 ng/mL in controls
Dosing
Not applicable (no dosing; single cross-sectional blood draw)
Route
Not applicable (endogenous measurement, no administration)
Duration
Cross-sectional (single time point)

Effects measured: Professional athletes had significantly LOWER serum MOTS-c than sedentary controls (p=0.0001), the opposite direction of an acute-exercise spike. This shows the human exercise-MOTS-c relationship is complex (chronic training associated with lower resting levels) and is correlational, not causal.

Side effects: No adverse events reported in this study

Sources: Alser M, et al. The Effect of Chronic Endurance Exercise on Serum Levels of MOTS-c and Humanin in Professional Athletes. Reviews in Cardiovascular Medicine. 2022.

How solid the evidence is

Evidence is dominated by ANIMAL work and is mostly from a single research group (Pinchas Cohen / Changhan Lee at USC) plus its collaborators, so it is not yet independently broad. The metabolic and exercise mouse studies (PMID 25738459, 31293078, 33473109) are consistent and use clear per-kg intraperitoneal dosing (0.5 to 15 mg/kg/day), but mouse mg/kg does not translate directly to a human dose, and group sizes in some arms are small. The single-dose performance study (PMID 35808870, 15 mg/kg) is a small rodent study (5-6 mice per group) and partly in rats. There was NO human interventional dosing trial of native MOTS-c until a Phase 2a study (NCT07505745, prediabetes and overweight/obesity, subcutaneous, still recruiting) began dosing in February 2026; before that, humans only appeared as observational data. Importantly the human evidence is mixed and partly contradictory: Reynolds (33473109) reports acute exercise transiently RAISES skeletal-muscle MOTS-c protein (measured by Western blot, 11.9-fold), while the athlete cross-sectional study (39077591) found serum MOTS-c was significantly LOWER in 75 professional endurance athletes than in 30 sedentary controls (with no significant difference between the lower- and higher-endurance athlete subgroups), which weakens any simple "more MOTS-c is better" narrative; that study does not state whether blood was drawn at rest, so it should be read as a single cross-sectional snapshot, not a resting-state comparison. Net: promising and mechanistically coherent in mice, but no completed human efficacy or safety dosing data yet, single-lab concentration for the mechanism-defining studies, and a notable human observational result pointing the opposite way. All PMIDs and citations were verified against NCBI records. As a sport-doping note (not an EU regulatory change), MOTS-c is on the WADA Prohibited List under S4.4.1 (metabolic modulators, AMPK activators), prohibited at all times in sport, named as an example since the 2025 list and still on the 2026 list, over a year before the first human dosing trial began.

Sources

Frequently asked questions

What is MOTS-c?

MOTS-c is a 16-amino-acid peptide encoded inside the mitochondrial 12S rRNA gene. In animal studies it activates the cellular energy sensor AMPK and is studied mainly for improving insulin sensitivity, reversing diet- and age-related metabolic decline, and boosting exercise/running capacity. In humans it is mostly studied as a naturally circulating peptide that rises with exercise, not yet as an administered drug.

Is MOTS-c legal to buy in the EU?

MOTS-c is sold strictly for laboratory research use. In the European Union it can be purchased as a research chemical, and it is not approved or intended for human or veterinary use. You are responsible for compliant handling in your country.

Where can I buy MOTS-c in Europe?

You can buy MOTS-c from PeptidesDirect, an EU-based shop that dispatches fast, tracked DHL parcels from within Europe. Every batch comes with a third-party Janoshik certificate of analysis (HPLC purity and mass-spectrometry identity), and selected batches also carry our own independent Liquilabs lab testing, all verifiable online before you buy.

Buy MOTS-c (for research use)

Study data, research use only. No established human dosing protocol.