MOTS-c sells on one word — mimetic. The pitch is that a peptide from the mitochondria can reproduce some of what exercise does, and the mouse data behind it are real and published in a major journal. What the pitch leaves out is the direction the human data run: in people, exercise makes MOTS-c. Nobody has published what happens when a person is given it. This page counts what exists, study by study; it reports research and gives no usage guidance, per our editorial standards.
What it is
MOTS-c is a 16-amino-acid peptide encoded not in the cell nucleus but in mitochondrial DNA, inside the gene for the 12S ribosomal RNA. A University of Southern California group described it in 2015, reporting that its main target appeared to be skeletal muscle, that it acted through the folate cycle to activate AMP-activated protein kinase (AMPK), and that in mice it prevented diet-induced obesity and age-related insulin resistance (Lee 2015, PMID 25738459). Its first story was metabolic, not muscular. The plain-language entry on what it is sits in Peptide Lexicon's MOTS-c entry; this page is about the performance question.
The performance evidence is five or six mice per group
The muscle-and-performance claim comes from one paper: Reynolds and colleagues, Nature Communications, 2021 (PMID 33473109). Read in full, it reports:
| Experiment | Animals | Result |
|---|---|---|
| Young mice, 5 mg/kg/day for 2 weeks | outbred CD-1 | Rotarod better; grip strength not improved |
| Young mice, normal diet, 0 / 5 / 15 mg/kg/day | n = 5, 5, 6 | Only 15 mg/kg ran longer and further |
| Young mice, high-fat diet, 5 and 15 mg/kg/day | small groups | 15 mg/kg improved running; all reached the sprint stage vs 16.6% at 5 mg/kg |
| Old mice, treatment started at 23.5 months, 3× a week | aged mice | Physical capacity and healthspan measures improved |
| Young mice | CD-1 | Lean mass increased |
The injections were intraperitoneal — into the abdominal cavity — which is a laboratory route, not the subcutaneous route the registered human trial uses. And the one strength test in the paper, grip, did not move. What moved was the capacity to keep running.
In humans, exercise raises MOTS-c — not the reverse
The paper's one human experiment points the other way. Ten sedentary young men (average age 24.5) cycled; biopsies and blood samples showed endogenous MOTS-c rose 11.9-fold in muscle after exercise, and about 1.5-fold in blood, returning to baseline in blood within four hours of rest.
Later human work is weaker still. A 2021 study randomised 30 people to endurance exercise, resistance exercise or rest and found MOTS-c showed only a trend to rise after endurance exercise, with plasma levels unrelated to fitness or leg strength (von Walden 2021, PMID 34351816). In 19 active men, repeated heat treatment during two weeks of ankle immobilisation raised circulating MOTS-c, but muscle thickness still fell with immobilisation (Elhusseiny 2025, PMID 40674654).
That is the whole human literature on MOTS-c and muscle: the peptide as a marker of activity, never as an intervention. The earlier comparison with AICAR, the other compound sold on an exercise-mimetic story, is on peptides for endurance.
The census
PubMed, 2026-09-23. MOTS-c[tiab] returns 257 records. Restricted to randomised-controlled-trial or clinical-trial publication types: 5. All five measure MOTS-c — after heat stress, after exercise in breast-cancer survivors, after acute exercise, during metformin treatment, and as a predictor of cardiac events in diabetes. None gives MOTS-c to anyone.
ClinicalTrials.gov, 2026-09-23. A text search for MOTS-c returns nine records, and a search of the intervention field alone returns five. Read one by one, eight of the nine measure it as a biomarker or match on unrelated text. One administers it:
- NCT07505745, Hudson Biotech — phase 2a, 120 adults with prediabetes and overweight, MOTS-c or placebo by subcutaneous injection for 12 weeks. Primary outcome: insulin sensitivity (Matsuda index) and adverse events. No muscle, strength or performance endpoint. Its start date, 2026-02-02, precedes its first submission, 2026-03-14. The same sponsor's TB-500 registration opens by describing itself as fictional, a finding recorded on the best peptide stack; this record carries no such statement, and each record has to be read on its own.
A search for the analogue CB4211 returns one completed phase 1a/1b trial, NCT03998514 (CohBar, 88 participants, healthy volunteers and people with fatty liver), with no results posted to the registry and no matching publication on PubMed.
Who ran the key study
The 2021 paper declares that two of its authors — including the senior author — were consultants and shareholders of CohBar, Inc., the company that developed CB4211. That does not make the mouse data wrong, and the paper disclosed it. It does mean the performance claim that drives MOTS-c's sales has so far been produced by the group with a commercial stake in the molecule, and has not been independently reproduced in humans.
What the doses mean, and what they do not
The mouse experiments used 5 and 15 mg/kg a day by intraperitoneal injection; only 15 mg/kg improved running. The standard body-surface-area arithmetic used to set first-in-human starting doses divides a mouse dose by about 12.3 (a human conversion factor of 37 against a mouse factor of 3, per Nair and Jacob 2016, PMID 27057123). Applied to 15 mg/kg, that gives about 1.2 mg/kg — roughly 98 mg a day for an 80 kg adult.
That figure is arithmetic about scale, not a dose. It shows only that the amount which worked in mice, translated by the convention regulators use for safety, is large. No human MOTS-c dose has been published, and the registered phase 2a trial does not state its amount in the public record. Peptifact's page on what circulates as MOTS-c dosing covers the figures in commerce.
Status in sport and at FDA
- WADA: named in S4.4.1 as an AMPK activator, alongside AICAR — a metabolic-modulator section, prohibited at all times. The section-by-section map is on WADA status by compound.
- FDA: not approved. On FDA's list of bulk substances nominated for compounding, MOTS-c is among the withdrawn nominations, set out with the 503A gates on peptide therapy.
The honest summary
- 257 PubMed records; 0 published trials that administer MOTS-c to a human.
- The performance data are mice, five or six per group, injected into the abdomen; grip strength did not improve.
- In humans, exercise raises MOTS-c — 11.9-fold in muscle in ten men.
- One registered human trial gives it, for insulin sensitivity, not muscle.
- The key paper's senior author held shares in the company developing an analogue, whose phase 1 trial has posted no results.
- Prohibited in sport at all times; not approved; nomination for compounding withdrawn.
Limits of this page
PubMed and registry counts depend on query wording and were taken on one date; a differently phrased search returns a slightly different set. The trial-type tags are the database's, and untagged human work may exist — none that administers MOTS-c turned up in the abstracts read. The CB4211 results may exist outside the registry and PubMed; this page reports only what those two sources hold.
Sources and dates
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015;21:443–54 — PMID 25738459
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021;12:470 — PMID 33473109, full text read 2026-09-23 incl. methods and competing-interests statement
- von Walden F, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol 2021;131:1035–42 — PMID 34351816
- 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;57:2764–74 — PMID 40674654
- Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7:27–31 — PMID 27057123
- PubMed, searched 2026-09-23:
MOTS-c[tiab]→ 257; with clinical-trial or RCT publication type → 5, all abstracts read. - ClinicalTrials.gov API v2, searched 2026-09-23:
MOTS-c→ 9 records (1 administers MOTS-c: NCT07505745);CB4211→ 1 (NCT03998514, no results posted). - World Anti-Doping Agency, Prohibited List, S4.4.1 — as mapped on this site's WADA status by compound.