MOTS-c
A peptide encoded in mitochondrial DNA, strong in mice, untested as a drug in people
MOTS-c is a 16-amino-acid peptide encoded by the mitochondrion's own genome. In mice, injected MOTS-c prevented diet-induced obesity and insulin resistance and improved physical capacity even when started late in life. None of the human studies below gave it to anyone: they measured the body's own levels, which rise with exercise and heat, and one genetic variant tracks diabetes risk.
What is it?
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. In 2015 a group reported that a short stretch of the mitochondrion's own DNA, inside the gene for its 12S ribosomal RNA, encodes a 16-amino-acid peptide that regulates insulin sensitivity and metabolic balance. Its main target appeared to be skeletal muscle, where it inhibits the folate cycle and the purine synthesis tied to it, which in turn activates AMPK, the cell's energy sensor.
Most of what is known comes from mice, and the mouse results are striking. Injections prevented both age-related and high-fat-diet insulin resistance and diet-induced obesity. In a 2021 study, MOTS-c improved physical performance in young, middle-aged and old mice, and intermittent treatment started at 23.5 months, very late in a mouse's life, increased physical capacity and healthspan. Later studies reported protection against muscle wasting during immobilisation and against gestational diabetes.
In people, MOTS-c has been measured rather than given. Exercise raised its levels in muscle and blood; a 16-week exercise programme raised it in non-Hispanic White breast-cancer survivors but not in Hispanic survivors; repeated heat exposure raised it in active men; and metformin did not change it. An Asian-specific variant that swaps one amino acid, K14Q, was linked to more type 2 diabetes in men in a meta-analysis of 27,527 people.
None of the carded studies gave MOTS-c to a human being, and a 2023 review notes that no effective method of applying it in the clinic has been developed. It is sold as a research chemical anyway. In the US, the Pharmacy Compounding Advisory Committee voted on July 23, 2026 to recommend it for the 503A bulks list; FDA has not acted, so pharmacies cannot compound it (as of September 26, 2026).
Mechanism of Action
MOTS-c is unusual in two ways: it is made from mitochondrial rather than nuclear DNA, and it appears to travel back into the nucleus to change which genes are read. The mechanisms below come from cells and mice. What happens when the peptide is injected into a person has not been studied in anything carded here.
The signalling and benefit steps come from cells and mice. In people, studies measure the body's own MOTS-c; none gave it as a treatment.
Each step is tagged with where it was shown. A dashed red arrow marks a link the evidence does not establish.
The pathway in words
- MOTS-c. A 16-amino-acid peptide encoded by a short open reading frame inside the mitochondrial 12S rRNA gene. Shown in: lab. Source: PubMed 25738459.
- AMPK and the nucleus. Under metabolic stress in cells it moved into the nucleus in an AMPK-dependent way and regulated antioxidant-response genes. Shown in: cells. Source: PubMed 29983246.
- Insulin sensitivity in mice. Acting mainly on skeletal muscle, it activated AMPK and, in mice, prevented age- and diet-related insulin resistance. Shown in: animals. Source: PubMed 25738459.
- Physical capacity in mice. It improved physical performance in young, middle-aged and old mice; started at 23.5 months, it extended healthspan. Shown in: animals. Source: PubMed 33473109.
- Levels in people. Circulating MOTS-c rose with exercise in some breast-cancer survivors and with repeated heat exposure in active men. Shown in: people. Source: PubMed 34413391, 40674654.
- never tested in people. Giving it to people. The human studies here measure the body's own MOTS-c or a gene variant; none gave the peptide as a treatment. Shown in: review. Source: PubMed 36761202.
Folate cycle to AMPK
In the discovery study, MOTS-c inhibited the folate cycle and the de novo purine synthesis tethered to it, which activated AMPK, the kinase that switches cells toward burning fuel. Skeletal muscle appeared to be the primary target. This is the basis of the 'exercise mimetic' label that later papers use, and it is a label, not a demonstrated effect in people.
Nuclear gene regulation
Under metabolic stress such as glucose restriction, MOTS-c moved into the nucleus in an AMPK-dependent way and regulated a broad set of genes, including those with antioxidant response elements. It interacted with NRF2, a transcription factor that controls antioxidant defences. The authors present this as evidence that the mitochondrial genome actively regulates the nuclear one.
Insulin sensitivity
In diet-induced obese mice, MOTS-c reduced three metabolic pathways that run high in obesity and type 2 diabetes: sphingolipid, monoacylglycerol and dicarboxylate metabolism. It improved insulin sensitivity and increased fat oxidation. A variant form, K14Q, lost the effect: obese male mice given it did not lose weight or improve glucose tolerance, and it sensitised cells to insulin less well.
Muscle under stress
At 15 mg/kg a day, MOTS-c limited muscle loss in immobilised mice to about 5%, against about 15% without it, and normalised signalling proteins tied to atrophy. The 2021 ageing study found it regulated genes for metabolism and protein maintenance and helped muscle cells adapt to metabolic stress. These results drive its sale for exercise and recovery.
Published Research
About 46 papers in our evidence set match MOTS-c, and the pattern is consistent: rich mouse and cell work, and human studies that only measure the body's own levels. The twelve cards below were chosen because their abstracts report what changed and by how much. Watch the type chip: 'Human' here means measurement, never treatment.
Discovery: a peptide coded by mitochondrial DNA
The paper that named MOTS-c. A short open reading frame inside the mitochondrial 12S rRNA gene encodes a 16-amino-acid peptide that regulates insulin sensitivity and metabolic balance, acting mainly on skeletal muscle. It inhibited the folate cycle and linked purine synthesis, activating AMPK. In mice, treatment prevented age-dependent and high-fat-diet insulin resistance and diet-induced obesity. The abstract reports no doses or effect sizes.
Into the nucleus under metabolic stress
Following metabolic stress, MOTS-c translocated to the nucleus in an AMPK-dependent manner and regulated a broad range of genes in response to glucose restriction, including genes with antioxidant response elements. It interacted with stress-responsive transcription factors such as NRF2. The authors argue that the mitochondrial and nuclear genomes co-evolved to regulate each other. It is a mechanism result, not a treatment study.
Better physical capacity in old mice
MOTS-c significantly enhanced physical performance in young (2-month), middle-aged (12-month) and old (22-month) mice, and intermittent treatment three times a week started at 23.5 months increased physical capacity and healthspan. It regulated nuclear genes tied to metabolism and protein maintenance. In people, the study found that exercise raises the body's own MOTS-c in muscle and blood. No human was given the peptide.
Plasma metabolites in obese mice
An unbiased metabolomics study in diet-induced obese mice found three pathways reduced after MOTS-c injection: sphingolipid, monoacylglycerol and dicarboxylate metabolism, all of which run high in obesity and type 2 diabetes models. The authors conclude that MOTS-c improves insulin sensitivity and increases beta-oxidation to prevent fat accumulation, which fits its reported effects on body weight and fatty liver in these mice.
A diabetes-linked variant in 27,527 people
An Asian-specific mitochondrial DNA variant, m.1382A>C, changes one amino acid of MOTS-c (K14Q). In a meta-analysis of three cohorts totalling 27,527 people, men but not women carrying it had more type 2 diabetes, and in one cohort only the least physically active men did. Obese male mice given normal MOTS-c lost weight and handled glucose better; mice given the K14Q form did not, and female mice were unaffected.
Exercise raised it in some cancer survivors
In a secondary analysis of a randomised trial, 25 Hispanic and 24 non-Hispanic White breast-cancer survivors did 16 weeks of aerobic and resistance exercise or usual care. MOTS-c rose significantly with exercise among non-Hispanic White survivors, where higher levels tracked falls in fat mass, weight, insulin resistance (HOMA-IR) and CRP and gains in lean mass, but not among Hispanic survivors. Levels were measured, not given.
Heat exposure raised circulating MOTS-c
Nineteen active men trained for four weeks, then had one ankle immobilised for two weeks while receiving repeated heat treatment (9 men) or a sham (10). Immobilisation did not change mitokine levels, but heat raised circulating MOTS-c (P = 0.033) and lowered FGF21 in muscle (P = 0.027). It suggests heat, like exercise, can raise the body's own MOTS-c. Nobody was given the peptide.
Metformin did not move it
Because metformin and MOTS-c share much of their mechanism, researchers measured circulating MOTS-c before and after 24 weeks in women with HER2-positive breast cancer randomised to neoadjuvant chemotherapy and trastuzumab with or without daily metformin. Neither regimen significantly changed MOTS-c levels, measured with a commercial ELISA. It is a useful negative: the overlap in mechanism does not mean metformin raises MOTS-c.
Less muscle lost during immobilisation
Ten-week-old male mice had a leg immobilised for eight days with or without daily MOTS-c at 15 mg/kg. Immobilisation cost about 15% of muscle mass; with MOTS-c the loss was about 5%. Treatment also normalised phosphorylated AKT and FOXO signalling linked to atrophy. For scale, 15 mg/kg a day is far above the community's 5–10 mg a week for an adult, and mouse doses do not convert one to one.
Gestational diabetes model in mice
Pregnant mice with diabetes induced by a high-fat diet and low-dose streptozotocin received MOTS-c daily during pregnancy. It significantly lowered blood glucose, improved insulin sensitivity and glucose tolerance, and reduced the high birth weights and offspring deaths the diabetes caused, with increased insulin sensitivity in skeletal muscle. Pregnancy is exactly where untested peptides are most dangerous, so this is a lead for trials, not a reason to self-treat.
Ovarian cancer: lower levels, slower tumours
MOTS-c levels were reduced in the serum and tumour tissue of ovarian cancer patients, and lower levels were associated with poorer prognosis. Added to ovarian cancer cells, MOTS-c slowed proliferation, migration and invasion and triggered cell-cycle arrest and apoptosis, by promoting the breakdown of the oncogenic protein LARS1. In mice it had a marked anti-tumour effect without systemic toxicity.
Therapeutic prospects, reviewed
This review describes MOTS-c as a 16-amino-acid peptide that moves to the nucleus during metabolic stress, circulates in plasma at levels that decline with age, and improves glucose metabolism in skeletal muscle, with possible relevance to diabetes, obesity and ageing. It also states plainly that MOTS-c has rarely been used to treat disease and that no effective method of applying it in the clinic has been developed.
What people say, and what was measured
MOTS-c is sold as exercise in a vial. The underlying science is genuinely interesting and almost entirely about what the body makes itself: every human finding below measures MOTS-c that people produced, not MOTS-c that anyone was given.
It mimics the effects of exercise, so it improves fitness and physical capacity.
Heard in: Frontiers in Endocrinology, MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation, which notes that MOTS-c has been used little in treatment and that no effective way to apply it in the clinic has been developed (read October 1, 2026). Source
The physical-capacity result is in mice: injections improved running performance in young, middle-aged and old animals, and treatment started late in life raised physical capacity. The human half of that same study found the opposite direction of causation — exercise raises the body's own MOTS-c, in muscle and in blood. Nobody has given MOTS-c to a person. PMID: 33473109
Shown in animals or cells onlyIt reverses insulin resistance and prevents the weight gain that comes with age.
Heard in: Grey Peptides listing review, October 1, 2026: listings present MOTS-c as a metabolic and insulin-sensitising peptide. Sellers are not named.
In mice. The paper that named MOTS-c in 2015 showed that treating mice prevented both age-related and diet-induced insulin resistance and diet-induced obesity, acting mainly on skeletal muscle through AMPK. Those are mouse experiments; the dose, the route and the effect in a person are all unknown. PMID: 25738459
Shown in animals or cells onlyLow MOTS-c causes diabetes, so taking it should prevent it.
Heard in: Aging Cell, A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide MOTS-c, which reports higher type 2 diabetes in men carrying a variant that weakens the peptide (read October 1, 2026). Source
Across 27,527 people, men carrying a MOTS-c variant had more type 2 diabetes, and among them only the least physically active did; women were unaffected. That is genetic evidence that the pathway matters. The treatment half of the same study was in mice, where MOTS-c improved glucose tolerance and the variant peptide did not. PMID: 33468709
Measured, never givenBlood levels of MOTS-c rise with exercise, which shows that supplementing it works.
Heard in: Frontiers in Endocrinology, MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation, which reviews the proposed applications in ageing, cardiovascular disease and insulin resistance (read October 1, 2026). Source
Exercise does raise it, and not in everyone. In a 16-week aerobic and resistance programme for breast cancer survivors, MOTS-c rose significantly in non-Hispanic White participants and not in Hispanic participants, with the rise tied to fat loss and better insulin resistance in the group where it occurred. A measurement that rises when you exercise is not evidence that injecting it reproduces the exercise. PMID: 34413391, 33473109
Measured, never givenEach claim is quoted from where it is said, never from a seller, and checked as of October 1, 2026 against the studies listed below.
Dosing Data
There is no human dose for MOTS-c, because none of the studies in our evidence set gave it to people. The community figure in our dataset, 5–10 mg injected weekly, comes from vendor charts and forums. The published mouse regimens are daily or several times a week at weight-based doses, such as 15 mg/kg a day in the immobilisation study, and none has been turned into a tested human protocol.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
→ Full MOTS-c dosage guide — why the community weekly dose has no trial behind it, and what the mouse studies actually used
→ Blend & Stack Calculator — MOTS-c is also sold in multi-peptide vials; the calculator shows what each draw delivers of every component; our blends and stacks hub sets out what each mix contains and what has been studied.
Side Effects & Contraindications
Reported Side Effects
We found no human adverse-event data for injected MOTS-c, because none of the studies in our evidence set gave it to people. The safety statements that exist come from mice, and the practical risks come from buying an unregulated research product.
Contraindications & Cautions
These cautions follow from what MOTS-c is reported to do in animals, not from observed harm in people, because there are no human treatment data to observe.
Legal Status
MOTS-c is not approved as a medicine in any of the jurisdictions below. It is sold as a research chemical, and in the US it is in the same limbo as the other peptides the Pharmacy Compounding Advisory Committee reviewed in July 2026: recommended, but not yet on any list a pharmacy may use. Status as of September 26, 2026.
Frequently Asked Questions
?Is MOTS-c made by the body?
Yes. It is encoded in the mitochondrion's own DNA, inside the gene for 12S ribosomal RNA, and it circulates in blood. A 2023 review notes that plasma levels decline with age. Exercise raised levels in muscle and blood in one study, and repeated heat exposure raised circulating levels in active men in another.
?Has MOTS-c been tested in humans?
Not as a treatment, in any study on this page. The human studies measured the body's own MOTS-c: after exercise, after heat, during metformin treatment, and in people carrying a diabetes-linked variant. Every result about taking MOTS-c comes from mice or cells.
?Does MOTS-c work like an exercise pill?
That is how it is marketed, and the mouse data explain why: it improved physical capacity in young and old mice and limited muscle loss during immobilisation. But in people, exercise raised MOTS-c, not the other way round, and nobody has shown that injecting it reproduces the benefits of training.
?Is MOTS-c safe?
There are no human safety data to answer that. A mouse cancer study reported no systemic toxicity. Because it improves insulin sensitivity in mice, low blood sugar is a theoretical risk, particularly alongside diabetes medication, and research-grade vials carry the usual contamination and dosing risks.
?Can a US pharmacy compound MOTS-c?
Not as of September 26, 2026. The Pharmacy Compounding Advisory Committee voted on July 23, 2026 to recommend adding it to the 503A bulks list, but FDA decides, through rulemaking, and has not done so. Until then no list allows a 503A pharmacy to compound it.
?What is the K14Q variant?
A version of MOTS-c with one amino acid changed, produced by an Asian-specific mitochondrial DNA variant (m.1382A>C). In a meta-analysis of 27,527 people, men carrying it had more type 2 diabetes, and in mice the K14Q form lost the weight and glucose benefits of normal MOTS-c.
References
- [pubmed] Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab, 2015;21(3):443-54. PMID: 25738459.
- [pubmed] 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;28(3):516-524.e7. PMID: 29983246.
- [pubmed] Reynolds JC, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun, 2021;12(1):470. PMID: 33473109.
- [pubmed] Kim SJ, et al. "The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity." Physiol Rep, 2019;7(13):e14171. PMID: 31293078.
- [pubmed] Zempo H, et al. "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c." Aging (Albany NY), 2021;13(2):1692-1717. PMID: 33468709.
- [pubmed] Dieli-Conwright CM, et al. "Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors." Sci Rep, 2021;11(1):16916. PMID: 34413391.
- [pubmed] Elhusseiny R, et al. "Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization." Med Sci Sports Exerc, 2025;57(12):2764-2774. PMID: 40674654.
- [pubmed] Cuyàs E, et al. "Circulating levels of MOTS-c in patients with breast cancer treated with metformin." Aging (Albany NY), 2022;15(4):892-897. PMID: 36490309.
- [pubmed] Kumagai H, et al. "Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration." Am J Physiol Endocrinol Metab, 2024;326(3):E207-E214. PMID: 38170165.
- [pubmed] Yin Y, et al. "The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus." Pharmacol Res, 2022;175:105987. PMID: 34798268.
- [pubmed] Yin Y, et al. "Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination." Adv Sci (Weinh), 2024;11(43):e2405620. PMID: 39321430.
- [pubmed] Zheng Y, et al. "MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation." Front Endocrinol (Lausanne), 2023;14:1120533. PMID: 36761202.
Sources & Citations
Every citation on this page is PubMed-indexed and has been checked against its record: not just that the identifier resolves, but that the paper is about what the sentence beside it claims. Where a 'Human' study measured the body's own MOTS-c rather than giving it, the card says so. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.