Peptide■America

Evidence review

MOTS-c: Mitochondria, No Human Outcomes

Does MOTS-c do in people what the exercise-mimetic marketing claims?

The answer

Not on any published evidence. The mechanism is real in mice; the five human trial-type records measure the body's own circulating MOTS-c after exercise, heat or metformin, or in a disease cohort, and not one administers the peptide to anyone.

Molecules
MOTS-c
US status
PCAC-recommended · pending
Sources
10
Reviewed
September 2026
MOTS-c in people: measured in them, never given to them

Every trial-type record measures a participant's own circulating MOTS-c after exercise, heat, metformin or in a disease cohort.

By Diane Walker · Reference Editor

What is MOTS-c, and what did the discovery paper show?

MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame inside the mitochondrial 12S ribosomal RNA gene, one of a small family of mitochondrial-derived peptides. The 2015 discovery paper reported that in mice it targets skeletal muscle, inhibits the folate cycle and de novo purine synthesis, activates AMPK, and prevented age-dependent and diet-induced insulin resistance as well as diet-induced obesity [1]. That is the origin of the exercise-mimetic label, and it is a mouse finding.

The animal literature has grown around it: 92 of the 254 indexed records carry the mice or rats subject headings [4]. The monograph records the regulatory position with the date it was verified; what has been done in people, and what has been done to them, is counted below.

How many human trials administer MOTS-c?

None. Searched in September 2026 across three names, PubMed returns 254 indexed records, 143 tagged Humans, 5 under the clinical-trial publication type and 4 under the randomized type [4]. All five were opened and read, and not one gives the peptide to a person; every one measures the participant's own circulating MOTS-c rather than administering the peptide [4].

The filters were proved live against a control term in the same session, and the reference records the counts beside the five [4]. The trial record prints the same five beside every other count in the index.

What do the five records actually measure?

A 2021 study randomized 30 subjects to a single bout of endurance exercise, resistance exercise or rest, ten to each, and measured circulating mitochondrial-derived peptides before and after; MOTS-c showed a trend upward after endurance exercise, and plasma levels were not correlated with fitness [5]. A second 2021 study ran a 16-week aerobic and resistance program in 49 breast cancer survivors, 25 Hispanic and 24 non-Hispanic White, and found that circulating MOTS-c rose after exercise in the non-Hispanic White group and not in the Hispanic group [6].

A 2025 study immobilized one ankle of 19 physically active men for two weeks and randomized them to repeated heat treatment or sham, nine and ten respectively; heat raised circulating MOTS-c (P = 0.033) while immobilization alone did not change it [7]. The remaining two are a 2022 study that measured circulating MOTS-c in breast cancer patients randomized to metformin and found no significant change, and a 2020 multicenter study that used the peptide as a predictor of outcome in diabetic patients with coronary disease [4].

Exercise, heat, metformin, prognosis. Each is a study of MOTS-c as a marker, a molecule the body makes more or less of in response to a stimulus; none is a study of MOTS-c as a treatment, a molecule injected to produce an effect. The distinction is the entire question a buyer arrives with, and the literature has not yet asked it.

Why does a marker not become a treatment?

Because a rise in an endogenous signal after exercise says nothing about what an injected dose of the same signal does, at what concentration, for how long, or with what off-target effect; those are the questions a first-in-human program exists to answer, and the record contains none. FDA's own entry for the substance says the same thing in regulatory language: the agency has not identified any human exposure data on drug products containing it administered via any route of administration, and lacks important information regarding any safety issues it raises, including whether it would cause harm if administered to humans [8].

That is the regulator stating the same absence the census above measures, and the two agree. A compound sold as an exercise mimetic on the strength of a mouse study and a human marker literature is a compound whose human exposure data, in FDA's words, do not exist.

What is the United States position, and what does a seller change?

MOTS-c left Category 2 of the interim 503A bulks list in April 2026 without Category 1 listing, and in July 2026 the Pharmacy Compounding Advisory Committee voted to recommend adding it to the section 503A list on a margin reported as 7–5 with two abstentions by McDermott Will & Schulte and by LumaLex Law, whose separate accounts agree substance by substance [2, 3]; the FDA has published no minutes, transcript or vote summary, so the figure is secondary wherever it is printed. The substance appears in no category of the list published on May 14, 2026 [9], and Drugs@FDA holds no application under the name, while the identical query returned an approved application for a control term in the same run [10].

The vote is advisory; the vote ledger carries the sourcing and the pending page explains what a recommendation changes, which is nothing until a final rule issues. Material offered under the name is research-use-only chemical supply outside pharmacy licensure, whatever the listing says, and a seller's existence does not alter a substance's status; the mitochondrial class sets this molecule beside NAD+, filed in this index as compoundable, for the clearest contrast the index offers.

Elsewhere in this index

Monographs

  • MOTS-cPCAC-recommended · pending

Topics

Reference tables

Sources

Every source below is inherited from a monograph in this index; this review introduces none of its own. The pointer beside each entry names the monograph and the reference number it came from.

  1. 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(3):443–454. PMID 25738459 Verified August 2026 on the mots-c monograph, reference 1.
  2. McDermott Will & Schulte. Bulk-list bound? PCAC backs majority of peptides in two-day public meeting. July 27, 2026. Read 2026-08-31. A secondary account, cited because the FDA has published no minutes, transcript or vote summary for the July 23–24, 2026 meeting; the agency's meeting page, content current as of August 6, 2026 and re-read on 2026-08-31, carries the briefing documents, the final agenda, the final meeting roster and the FDA presentations, and no record of any vote. This report gives the tally for each substance and states that FDA scientists recommended against inclusion in each instance. Source Verified August 2026 on the mots-c monograph, reference 2.
  3. LumaLex Law. The July 2026 PCAC Peptide Meeting. July 25, 2026. Read 2026-08-31. A second, independent secondary account, checked against the first: it prints all seven July 23–24, 2026 votes as a table — BPC-157, KPV and TB-500 at 8–6–1, MOTS-c at 7–5–2, Semax at 8–5–1, Epitalon at 7–4–1, and emideltide (DSIP) at 6–7–1 — and the two accounts agree substance by substance. Source Verified August 2026 on the mots-c monograph, reference 3.
  4. PubMed, National Library of Medicine. Census run 2026-09-01 across three name variants — "MOTS-c" OR "MOTS-C peptide" OR "mitochondrial open reading frame of the twelve S rRNA type-c" — returning 254 indexed records, 143 carrying the Humans MeSH term, 5 under "clinical trial"[Publication Type] and 4 under "randomized controlled trial"[Publication Type]; 92 records carry the mice or rats MeSH terms, and 25 carry both the term exercise and the Humans term. All five trial-type records were opened and read, and not one administers the peptide: a 2020 multicenter study using circulating MOTS-c as a predictor of outcome in diabetic patients with coronary disease, a 2021 study of circulating MOTS-c after a single bout of endurance or resistance exercise, a 2021 study of circulating MOTS-c after a 16-week exercise program in breast cancer survivors, a 2022 study of circulating MOTS-c in breast cancer patients randomized to metformin that found no significant change, and a 2025 study of circulating MOTS-c after repeated heat exposure during limb immobilization. The publication-type filter was proved live in the same run against a control term returning 8,906 records under the clinical-trial type and 6,115 under the randomized type; the invalid tag clinicaltrial[pt] returned 0 for that control term, and a deliberately invalid record identifier errored at the start and the end of the run. The counts reproduce the 2026-08-31 run behind the trial-record table exactly. Source Verified September 2026 on the mots-c monograph, reference 4.
  5. von Walden F, Fernandez-Gonzalo R, Norrbom J, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021;131(3):1035–1042. PMID 34351816 Verified September 2026 on the mots-c monograph, reference 5.
  6. Dieli-Conwright CM, Sami N, Norris MK, 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 Verified September 2026 on the mots-c monograph, reference 6.
  7. Elhusseiny R, Ihsan M, Labidi M, 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 Verified September 2026 on the mots-c monograph, reference 7.
  8. US Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks, content current as of April 22, 2026, table of bulk drug substances nominated but withdrawn, entry for MOTs-C (the page's spelling). Read 2026-09-01. The entry states that compounded drugs containing the substance may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization, that FDA has not identified any human exposure data on drug products containing it administered via any route of administration, and that FDA lacks important information regarding any safety issues it raises, including whether it would cause harm if administered to humans. Source Verified September 2026 on the mots-c monograph, reference 8.
  9. US Food and Drug Administration. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act, updated May 14, 2026. Read in full 2026-09-01: "MOTS" occurs nowhere in the document, so the substance appears in none of Category 1, Category 2, or Category 3. Control in the same read: the same document names GHK-Cu six times. Source Verified September 2026 on the mots-c monograph, reference 9.
  10. US Food and Drug Administration, Drugs@FDA through the openFDA drugsfda endpoint. Queried 2026-09-01 on the generic name, the substance name and the brand name for "MOTS-c": no matching application. Control in the same run: the identical query for "bremelanotide" returned NDA 210557. Source Verified September 2026 on the mots-c monograph, reference 10.