Nine MOTS-c Trials, One That Administers the Peptide

From mitochondrial DNA to the folate cycle and AMPK

MOTS-c is unusual because its coding origin is mitochondrial rather than nuclear. The 2015 discovery study describes a 16-residue peptide encoded by a 51-base-pair short open reading frame within the mitochondrial 12S rRNA region. In HEK293 cells and mice, the researchers found inhibition of the folate cycle and linked de novo purine biosynthesis, an increase in AICAR, and activation of AMPK. Their mouse insulin-sensitivity experiments identified skeletal muscle as the principal target tissue.

The sequence hangs together: folate-cycle inhibition changes purine synthesis, AICAR rises, AMPK switches on. All of it is cell and mouse work. No completed human study has followed that chain in people, because until February 2026 no registered study administered the peptide at all.

A 2021 study of exercise and aging added changes in nuclear genes related to metabolism and proteostasis, skeletal-muscle metabolism, and myoblast stress adaptation. It also observed exercise-associated increases in endogenous MOTS-c in human skeletal muscle and circulation. Those human observations followed the body's own peptide levels during exercise; participants were not given MOTS-c.

For a receptor-based comparison with other metabolic compounds in the catalogue, retatrutide vs. tirzepatide vs. semaglutide maps how their targets differ from one another.

What the mouse protocols actually administered

The metabolic findings most often associated with MOTS-c come from named mouse experiments with defined schedules. In the 2015 mouse study, researchers administered 5 mg/kg/day split into two daily administrations for four days in an acute normal-diet experiment. They also administered 5 mg/kg/day intraperitoneally for seven days in insulin-sensitivity experiments, and 0.5 mg/kg/day intraperitoneally for three or eight weeks in high-fat-diet experiments. The study reported improved glucose handling and prevention of high-fat-diet-induced obesity and insulin resistance in mice.

The 2021 physical-performance study administered 5 or 15 mg/kg/day intraperitoneally in young, middle-aged, and old mice. A late-life intermittent experiment used 15 mg/kg/day three times weekly. The reported physical-performance effects belong to those mouse protocols, while the human component measured endogenous MOTS-c around exercise.

These amounts describe experimental administration to mice. They do not supply a human protocol, and MOTS-MET's fixed daily amount remains undisclosed. The 10 mg catalogue size is a product variant, not the numeric dose used in that study. Researchers working with catalogue material can separately consult Curo's guide to storing research peptides and bacteriostatic water.

K14Q links a human cohort signal to mouse experiments

The mitochondrial DNA variant m.1382A>C, rs111033358, produces a Lys14Gln substitution, abbreviated K14Q. In the 2021 K14Q study, a meta-analysis across the J-MICC, MEC, and TMM cohorts included 27,527 participants. The C allele was associated with higher type 2 diabetes prevalence in men, but not in women.

The same paper extended the variant work into mice. One experiment administered wild-type or K14Q peptide at 7.5 mg/kg intraperitoneally twice daily for 21 days; another used 0.5 mg/kg intraperitoneally daily for 21 days. In mice carrying the variant, the calculated clearance rate for K14Q was 2.6-fold slower than for wild-type MOTS-c after intraperitoneal osmotic-pump administration.

The cohort finding is a genetic association in people, not a result from giving anyone the peptide. The clearance figure is relative and comes from mice, so it is not a human half-life. One detail is worth getting right, because it circulates wrongly: the substitution is K14Q, not K14R. What the K14Q work does is make a single residue matter to MOTS-c biology in humans and mice at once. What it does not do is tell you what an administered dose does. Human clearance, bioavailability, distribution, metabolism and excretion are all still open.

A 7-5 recommendation, with the trial still running

The Federal Register notice published April 16, 2026 put MOTs-C free base and MOTs-C acetate in front of FDA's Pharmacy Compounding Advisory Committee on July 23, 2026, under docket FDA-2025-N-6895, naming obesity and osteoporosis as the evaluated uses.

The committee recommended both forms for the Section 503A bulks list, by the narrowest margin of the two-day meeting: 7 in favor to 5 against, with two abstentions on each form. Hyman, Phelps & McNamara described it as a 7-5-2 margin, and Pharmaceutical Executive and McDermott Will & Schulte published the same figures. FDA's staff had argued the other way, its briefing document citing no human safety or effectiveness information alongside unresolved characterization and immunogenicity questions.

Read that against the registry and the two records sit oddly together. The committee weighed a compounding question in July 2026 while the only study that administers MOTS-c to people was five months into enrolment with nothing reported. The recommendation is also advisory: FDA is not bound by it, and listing happens through rulemaking. FDA's meeting page holds the briefing documents, the questions and the archived broadcast, but no minutes or vote table.

For contrast on what a finished registry record looks like, follow Ipamorelin: a secretagogue that finished its trials.

Common questions

How many MOTS-c clinical trials actually give participants MOTS-c?

One. NCT07505745, MOTS-MET, administers a fixed subcutaneous dose once daily for 12 weeks. The other eight records measure MOTS-c as a biomarker or outcome.

What dose does the MOTS-MET human study use?

The MOTS-MET registry record describes a fixed daily subcutaneous dose but does not disclose the numeric amount. The 10 mg catalogue variant should not be read as the study dose.

Is MOTS-c FDA approved?

No. FDA's substance record for UNII A5CV6JFB78 identifies MOTS-c and expressly says that a UNII does not imply regulatory review or approval.

What is the strongest evidence worth reading first?

Start with the mitochondrial-origin and folate-cycle/AMPK work, then the mouse metabolic and exercise protocols, and finally the K14Q cohort analysis. The human administration program becomes more informative when MOTS-MET posts results.