MOTS-c Peptide: Benefits, Side Effects and the Evidence
What Is MOTS-c, and Where Does It Come From?
MOTS-c is a peptide of 16 amino acids, the building blocks of proteins, encoded in mitochondrial DNA. Mitochondria are the parts of a cell that turn fuel into energy. In mice on a high-fat diet, MOTS-c treatment reduced weight gain and prevented insulin resistance. The FDA found no clinical studies or human exposure data for MOTS-c given by any route.
Most genes sit in the cell's nucleus, but this one sits in the mitochondria's own DNA. The peptide was first described in Lee 2015. The team found a short gene inside the 12S rRNA region, a stretch of mitochondrial DNA. The authors say the peptide must be built in the cytoplasm, the fluid that fills the cell, which suggests its genetic message leaves the mitochondria. They detected MOTS-c in several mouse and rat tissues and in human and rodent blood. Humanin is the other well-known peptide made from mitochondrial DNA. Lee 2016, a review by the same team, says MOTS-c targets skeletal muscle and boosts glucose metabolism.
Zheng 2023 is a review of the biology. It says MOTS-c moves into the nucleus during metabolic stress. There it directs the expression of nuclear genes. The same review notes that blood levels of MOTS-c fall with age. It also cites studies in which MOTS-c, working with Nrf2 (a protein that switches on protective genes), raised the expression of genes that protect mitochondria. Because it acts both inside cells and through the blood, Reynolds 2021 notes that it has been dubbed a mitochondrial-encoded hormone.
How Does MOTS-c Work in the Body?
In cell studies, MOTS-c switches on AMPK, an enzyme that acts as the cell's energy sensor. Lee 2015 traced the route. MOTS-c slows the folate cycle, a chain of reactions that helps cells make purines, the building blocks of DNA. A molecule called AICAR then builds up, and AICAR turns on AMPK. This is the folate-AICAR pathway. Blocking AMPK in cells cut the effect only in part, so AMPK is not the whole story.
In mice on a high-fat diet, MOTS-c raised AMPK activity and GLUT4 levels in muscle. GLUT4 is a transporter that moves glucose into muscle cells. Kim 2019 calls MOTS-c an exercise mimetic, meaning something that copies part of what exercise does.
Wan 2023, a review, describes this retrograde signalling, meaning messages sent from the mitochondria back to the nucleus. It says MOTS-c moves to the nucleus under metabolic stress, and that exercise raises MOTS-c levels. There it controls genes that carry antioxidant response elements. These are gene switches that help cells cope with oxidative stress, the damage done by reactive oxygen molecules. Gao 2023, another review, links the effects of MOTS-c to genes such as GLUT4, STAT3 and IL-10. STAT3 and IL-10 are signals tied to inflammation.
The FDA's 2026 review of MOTS-c adds a caution. It says the molecular targets behind its effects "remain unknown." That makes it hard to predict which organs MOTS-c affects.
What Are the MOTS-c Benefits the Research Shows?
Every benefit below comes from mice or cells. The FDA review says animal studies of MOTS-c have been limited to rodent models. It calls their clinical relevance "currently unknown."
In Lee 2015, mice on a high-fat diet got MOTS-c at 0.5 mg per kg of body weight a day. It was injected into the belly. They gained less weight than mice on the same diet without MOTS-c. Food intake was the same in both groups. The treated mice had less fat in the liver and lower insulin levels. They also gave off more body heat, which the authors link to higher energy use.
The same study used a clamp test. It measures the glucose infusion rate, meaning how much glucose must be dripped in to keep blood sugar steady while insulin is raised. After 7 days of MOTS-c, mice needed roughly 30% more glucose. That points to better whole-body insulin sensitivity. Insulin-driven glucose disposal rose, which the authors read as better muscle insulin sensitivity, while glucose output from the liver did not change.
Kim 2019 looked at blood chemicals in mice made obese by diet. After MOTS-c, three pathways fell: sphingolipid, monoacylglycerol and dicarboxylate metabolism. These fat-handling pathways run higher in obese and type 2 diabetes models. The authors report that MOTS-c raised beta-oxidation, the burning of fat for fuel, which limited fat build-up.
Can the MOTS-c Peptide Improve Exercise Performance?
In mice, MOTS-c treatment improved running. No study has tested whether MOTS-c improves exercise performance in people.
Reynolds 2021 measured MOTS-c in 10 sedentary young men during a hard cycling session. In thigh muscle, levels rose about 11.9-fold after exercise. In blood, they rose 1.6-fold during exercise and 1.5-fold after it. Blood levels were back to baseline after 4 hours of rest.
In the same paper, mice got MOTS-c by injection into the belly. Old mice given 15 mg per kg a day for 2 weeks ran 2-fold longer than untreated old mice. They also ran 2.16-fold farther. From about 23.5 months of age, old mice got 15 mg per kg three times a week. Near the end of life, they had better grip strength, stride length and walking ability.
Hyatt 2022 found that 4 to 8 weeks of voluntary running raised MOTS-c protein about 1.5 to 5-fold in rodent leg muscles. In untrained mice, a single 15 mg per kg dose raised total running time by 12% and distance by 15% in one exercise test. Yoon 2022, a review, frames this as mitohormesis. That is the idea that a mild mitochondrial stress triggers helpful changes in the body.
A separate trial gave 30 people endurance exercise, resistance exercise or rest, 10 in each group. Blood MOTS-c showed only a trend to rise after endurance exercise. Resistance exercise did not raise these peptides (von Walden 2021).
What Does MOTS-c Do for Recovery and Muscle?
The evidence on MOTS-c and muscle comes from cells and mice. None of it shows recovery in people.
Elhusseiny 2026 grew human muscle cells in a dish. These myotubes are lab-grown muscle fibres. The cells were exposed to dexamethasone, a glucocorticoid, an anti-inflammatory drug that causes muscle wasting. Adding MOTS-c completely preserved the size of the cells. It raised Akt activity, a growth signal. It also blunted MURF1 and STAT3, two drivers of muscle breakdown.
Jia 2024 found that in people, MOTS-c levels tracked mitochondrial content. They also tracked TRIM72, a protein that repairs damaged cell membranes. In cell and mouse work, MOTS-c helped move TRIM72 to the damaged membrane. In mice lacking TRIM72, MOTS-c did not rescue membrane injury, though it still increased vesicle fusion with the membrane.
In a rodent (mouse) study, the hind limbs were immobilised with casting tape for 8 days. That cut muscle mass by about 15%. Mice given MOTS-c by injection at 15 mg per kg a day lost only about 5%. Muscle fatty acid levels were also lower with MOTS-c than in casted mice without it (Kumagai 2024).
Jiang 2023 studied mice with pain after a nerve injury. MOTS-c reduced the pain, and a drug that blocks AMPK stopped that effect. MOTS-c also calmed microglia, the immune cells of the spinal cord. But pain relief held even when microglia were blocked. So the authors say microglia are not needed for it. In the spinal cord, MOTS-c cut oxidative damage mainly in nerve cells.
What Do Human Trials of MOTS-c Show So Far?
No human trial of MOTS-c itself has published results. The FDA's 2026 review found no clinical studies or human exposure data for MOTS-c by any route. A related compound, CB4211, has been tested in people. CohBar, the company behind it, called it an analogue of MOTS-c, meaning a modified version, in a 2022 annual report.
We searched PubMed on 16 October 2026 for MOTS-c[tiab] AND clinicaltrial[filter]. It returned 5 records. All five measured the body's own MOTS-c levels, and none gave MOTS-c to people.
The CB4211 trial is registered as NCT03998514. It was a Phase 1a/1b study, an early safety trial, with 88 people enrolled. Two parts tested single doses and 7 days of daily doses in healthy adults who were not obese. A third part gave once-daily doses under the skin for 28 days. That part enrolled people with obesity and nonalcoholic fatty liver disease, a build-up of fat in the liver not caused by alcohol. The registry shows no posted results.
CohBar's annual report gave these Phase 1b results.
| CB4211 Phase 1b measure | CB4211, 25 mg (11 people) | Placebo (9 people) |
|---|---|---|
| ALT, a liver enzyme | 21% fall | 4% rise |
| AST, a liver enzyme | 28% fall | 11% fall |
| Glucose | 6% fall | No change |
The company marked all three as statistically significant against placebo. It said CB4211 was well tolerated, with no serious adverse events. People in the Phase 1a part had mild but persistent injection-site reactions. The company described them as painless bumps under the skin. The data were presented at a 2021 liver meeting, and we found no peer-reviewed paper on them. Those are early-stage numbers from a small trial, reported by the company. CB4211 is a modified analogue rather than native MOTS-c. So the figures are a signal of direction, not a guarantee of effect. CohBar said it planned to find a partner before any further trials.
What MOTS-c Before and After Results Are Realistic?
No published study shows MOTS-c before and after results in people.
What the published work measured is narrower. Mice ran longer and further. Mice on a high-fat diet gained less weight without eating less. In the CB4211 trial, people on the analogue had lower liver enzymes and glucose. Nobody has published a human before and after on body composition using native MOTS-c. There is no honest figure to quote for that.
How Much MOTS-c Do Studies Actually Use?
No study has tested a MOTS-c dose in people. Every dose in the table comes from mice, or from the CB4211 analogue trial. Mouse doses are given per kg of body weight. None of them is tied to a safe or useful dose in people. Our MOTS-c dosage guide covers the topic separately.
| Source | Who | Route | Dose (as reported) |
|---|---|---|---|
| Lee 2015 | Mice on a normal diet | Into the belly | 5 mg per kg a day, given in two doses, for 4 days |
| Lee 2015 | Mice on a high-fat diet | Into the belly | 0.5 mg per kg a day |
| Kim 2019, as reported by the FDA | Mice made obese by diet | Into the belly | 2.5 mg per kg twice a day for 3 days |
| Reynolds 2021 | Young, middle-aged and old mice | Into the belly | 5 or 15 mg per kg a day; old mice 15 mg per kg a day for 2 weeks |
| Reynolds 2021 | Old mice, from late life | Into the belly | 15 mg per kg, three times a week |
| Kumagai 2024 | Mice immobilised with casting tape | By injection | 15 mg per kg a day for 8 days |
| Hyatt 2022 | Untrained mice | Into the belly | 15 mg per kg, once, 10 minutes before an exercise test |
| CB4211 trial, per CohBar and the registry | Adults with obesity and fatty liver | Under the skin | 25 mg, once a day for 28 days (CB4211, not MOTS-c) |
| Pharmacy nomination, per the FDA | No one. These are product sizes. | Under the skin (proposed) | 5 mg and 10 mg products |
The FDA notes that the animal studies did not test dose-response, meaning how an effect changes as the dose changes. A lab study cited by the FDA found MOTS-c breaks down quickly in human blood. The FDA says it is unclear whether an injection could reach active levels over time. Lee 2015 compares MOTS-c with metformin, a diabetes drug that also acts on AMPK and the folate cycle.
What Are the MOTS-c Side Effects?
MOTS-c side effects in people are unknown. The FDA found no clinical studies or human exposure data for MOTS-c by any route. It concluded that the potential safety risks in humans are unknown. MOTS-c is not part of any FDA-approved drug. A search of the FDA's adverse event database through March 2025 found no reports for MOTS-c. The FDA notes that compounding pharmacies generally do not report adverse events to it.
The FDA is particularly concerned about the lack of human data. It is also concerned about immunogenicity, the risk of the immune system reacting to the peptide. It says this risk may be higher when a peptide is injected under the skin. It also flags possible impurities and aggregates, which are clumps of peptide. The FDA found no animal toxicity studies of MOTS-c.
For the CB4211 analogue, the company reported no serious adverse events. People in the Phase 1a part had mild but persistent injection-site bumps. The company says it saw no persistent bumps after it changed the formulation partway through that part. In that trial, the fatty liver part tracked side effects for up to 12 weeks, per the registry. We found no human safety data for MOTS-c or CB4211 over a longer period. Want the detail on checking a supplier's testing claims? Read our guide on how to know if peptides are real.
Is MOTS-c Legal, and Is It Banned in Sport?
MOTS-c is not approved by the FDA for human use. In its review dated 11 May 2026, the FDA proposed not adding MOTS-c to the 503A bulks list. That is the list of substances pharmacies may use to compound drugs, meaning custom-make them. It was on the agenda of an FDA advisory panel meeting held on 23-24 July 2026. The briefing says the FDA will not make a final decision until it has weighed the panel's advice. We found no vote record on the meeting page.
The FDA also lists MOTS-c on its page of bulk substances that may pose safety risks in compounding. It sits in the group whose nominations were withdrawn. A nomination is a request to allow a substance for compounding.
In sport, the FDA review notes that MOTS-c is listed as prohibited in the Global DRO database. That listing draws on the 2024 Prohibited List of the World Anti-Doping Agency (WADA), under hormone and metabolic modulators.
How Does MOTS-c Compare With Other Peptides?
MOTS-c is studied mainly for metabolism and exercise, in mice and cells. The table sets out what each peptide is studied for and what we know about human data.
| Peptide | Mainly studied for | Human data |
|---|---|---|
| MOTS-c | Insulin sensitivity, body weight and running, in mice | FDA found no clinical studies or human exposure data |
| GHK-Cu | Not covered on this page | See our GHK-Cu guide |
| BPC-157 | Not covered on this page | FDA, 2026: "insufficient clinical safety information" |
| TB-500 | Nominated for wound healing (FDA, 2026) | FDA, 2026: no clinical studies or human exposure data by any route |
| Humanin | Same mitochondrial origin; Lee 2015 says it protects nerve and blood vessel systems | Not covered on this page |
The comparison rests on how each peptide has been studied, not on proof that any of them works in people.
How Do You Check a MOTS-c Supplier's Testing?
No MOTS-c product is FDA-approved, so its quality depends on who made it. The FDA found MOTS-c is not well characterised. It found no published quality-control data on its impurities, aggregates or endotoxins, which are toxins from bacteria. A certificate of analysis is a lab report on one batch. HPLC is a lab test that measures purity. Our guide on how to read a peptide COA shows what a real one looks like.
We keep a running, vendor-neutral list of what to check on our recommended sources page. A test report shows what is in a vial. It does not show that MOTS-c is safe or that it works in people.
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Where to buy MOTS-c
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- Lee et al. 2015, The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
- Zheng et al. 2023, MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation
- Lee et al. 2016, MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism
- Wan et al. 2023, Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging
- Gao et al. 2023, MOTS-c Functionally Prevents Metabolic Disorders
- Kim et al. 2019, The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity
- Reynolds et al. 2021, MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
- Hyatt 2022, MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose
- von Walden et al. 2021, Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
- Kumagai et al. 2024, Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration
- Yoon et al. 2022, Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c)
- Elhusseiny et al. 2026, Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells
- Jia et al. 2024, Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane
- Jiang et al. 2023, Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice
- FDA 2026, Briefing document for MOTS-c-related bulk drug substances, Pharmacy Compounding Advisory Committee, 23-24 July 2026
- FDA, Certain bulk drug substances for use in compounding that may present significant safety risks
- FDA 2026, Briefing document for BPC-157-related bulk drug substances; briefing document for TB-500-related bulk drug substances
- ClinicalTrials.gov, NCT03998514: A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease
- CohBar, Inc., Annual report (Form 10-K) for 2021, filed 29 March 2022
This content is for educational purposes only and is not medical advice. Nothing here is a guide to research use or to treatment. A qualified clinician can advise on any health decision.
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Frequently Asked Questions
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Disclaimer: This content is for educational purposes only. These compounds are intended for research use. Nothing here is medical advice. Always work with a qualified clinician before making changes to your health protocol.