MOTS-c peptide

Summary

MOTS-c is a 16 amino acid peptide encoded by mitochondrial DNA (the separate genetic code inside the cell's energy-producing mitochondria) that acts as a metabolic signal. In mice it activates AMPK, the cell's energy sensor, prevents diet induced obesity and insulin resistance, and improves exercise capacity and physical decline with age, but human evidence is limited to circulating levels that rise with exercise and a genetic variant linked to diabetes risk, with no published human treatment trial. FDA removed it from the 503A Category 2 list (compounding ingredients flagged for significant safety risks) in April 2026 and the Pharmacy Compounding Advisory Committee (FDA's outside expert panel) recommended it for the 503A bulks list (ingredients pharmacies may use to compound drugs for individual patients) in July 2026; no final rule has been published.

What is MOTS-c?

MOTS-c is a mitochondrial derived peptide (16 amino acids) encoded in the 12S rRNA region of mitochondrial DNA. It is also known as Mitochondrial open reading frame of the 12S rRNA type-c, MOTS c, Mitochondrial derived peptide MOTS-c, MOTS-c peptide, MOTSc, MOTS c peptide.

How does it work?

MOTS-c is translated from a short open reading frame inside the mitochondrial 12S rRNA gene. In cells and mice it inhibits the folate cycle and de novo purine synthesis, which raises AICAR and activates AMPK, increasing glucose uptake and fatty acid oxidation in skeletal muscle. Under metabolic stress it moves into the nucleus and regulates stress response genes. Circulating levels in people rise acutely with exercise and fall with age. All mechanistic work is in cells and rodents.

MOTS-c benefits: what the evidence shows

The foundational 2015 mouse study showed that MOTS-c injection prevented high fat diet induced obesity and insulin resistance and improved glucose handling in aged mice. A 2021 study showed that circulating MOTS-c rises with exercise in young men and that treating mice, including old mice, improved running capacity and physical performance. Human data are observational: an East Asian mitochondrial DNA variant that changes the MOTS-c sequence is associated with type 2 diabetes in men. No human interventional trial of MOTS-c has been published, and a phase 1 study of a related analog by a former sponsor was never published in a peer reviewed journal. The human study is a genetic association study, not an intervention with the peptide; it is listed but does not raise the grade.

Human evidence

No indexed human treatment trial identified. Reynolds et al. 2021 measured MOTS-c in skeletal muscle and plasma of 10 healthy young men before and after exercise and found it rose acutely. Zempo et al. 2021 reported that the m.1382A>C mitochondrial DNA variant, which substitutes lysine 14 with glutamine in MOTS-c, was associated with type 2 diabetes in Japanese men and reduced the peptide's metabolic activity in cells. These are correlational findings, not treatment effects.

Animal evidence

Lee et al. 2015: daily intraperitoneal MOTS-c (0.5 mg/kg) prevented weight gain and insulin resistance in mice on a high fat diet and improved insulin sensitivity in aged mice, working through AMPK activation in skeletal muscle. Reynolds et al. 2021: MOTS-c treatment (15 mg/kg) improved treadmill running in young, middle aged, and old mice, and late life treatment improved physical capacity and some healthspan measures.

Key studies

Conditions studied

Is MOTS-c legal in the United States?

FDA and compounding status

MOTS-c was placed on the FDA 503A Category 2 list (substances with significant safety risks) in 2023 and removed from it on April 15, 2026. On July 23 to 24, 2026 the Pharmacy Compounding Advisory Committee recommended adding MOTS-c to the 503A bulks list. As of the last verification date FDA has not published a final rule, so compounding pharmacies and state boards vary in whether they will fill it. It is not an FDA approved drug and is not eligible for 503B outsourcing.

WADA status

WADA prohibited. Athletes subject to anti-doping testing should treat this as prohibited at all times unless the current prohibited list says otherwise.

Regulatory timeline

1. Sep 21, 2026WADA

   WADA publishes the 2027 Prohibited List

   WADA published the 2027 Prohibited List on September 21, 2026, and it takes effect January 1, 2027. The S2 peptide hormone and growth factor classes are unchanged. BPC-157 is still named under S0, and MOTS-c is still named under S4.4 as an activator of AMP-activated protein kinase. WADA added a note that many peptides without approval for human use fall under S0 or another section, and that a peptide not named on the list may still be prohibited. GLP-1 receptor agonists such as semaglutide and tirzepatide are still not on the list.

   Source: WADA 2027 Prohibited List
2. Jul 23, 2026PCAC

   PCAC recommends six peptides for the 503A bulks list

   At its July 23 to 24, 2026 meeting, FDA's Pharmacy Compounding Advisory Committee voted to recommend that BPC-157, KPV, TB-500, MOTS-c, semax, and epitalon be added to the 503A bulk drug substances list. A committee recommendation is advisory; FDA must still issue a rule before the substances are formally listed.

   Regulatory: Under FDA reviewSource: Pharmacy Compounding Advisory Committee
3. Apr 15, 2026FDA

   FDA lists BPC-157 and 16 other peptides as withdrawn from 503A Category 2

   FDA's Category 2 page, revised in April 2026 and current as of April 22, 2026, moved BPC-157, AOD-9604, CJC-1295, dihexa, DSIP, epitalon, injectable GHK-Cu, ipamorelin, KPV, LL-37, melanotan II, MOTS-c, PEG-MGF, selank, semax, thymosin alpha-1, and thymosin beta-4 fragment (TB-500) to a list of bulk drug substances nominated but withdrawn by their nominators. A withdrawn substance is no longer in 503A Category 2, but withdrawal is not an approval and does not place a substance on the 503A bulks list; a 503A pharmacy still needs a listing before it may compound it. Ipamorelin acetate remains in 503B Category 2. Seven of the withdrawn peptides (BPC-157, KPV, TB-500, MOTS-c, semax, epitalon, and DSIP) were taken to the Pharmacy Compounding Advisory Committee in July 2026.

   Regulatory: Removed from Category 2 (Apr 2026)Source: FDA: Certain bulk drug substances for use in compounding may present significant safety risks (503A and 503B Category 2 lists and withdrawn nominations, content current as of April 22, 2026)
4. Jan 1, 2026WADA

   WADA 2026 Prohibited List takes effect

   The 2026 WADA Prohibited List took effect on January 1, 2026 and continues to prohibit the S2 peptide hormone and growth factor classes (GHRH analogs, growth hormone secretagogues, GH fragments, IGF-1 and analogs, MGF, thymosin beta-4 and derivatives, hCG and GnRH-class releasing factors in males), myostatin inhibitors, insulin and the AMPK activator MOTS-c under S4, desmopressin under S5, and BPC-157 under S0. GLP-1 receptor agonists such as semaglutide and tirzepatide are not on the list.

   Source: WADA Prohibited List
5. Sep 2023FDA

   FDA places a batch of nominated peptides in 503A Category 2

   In September 2023 FDA updated its 503A bulk drug substances category lists to place a group of nominated peptides in Category 2, which means FDA identified significant safety risks and the substances may not be used in 503A compounding while the evaluation continues. Kisspeptin-10 and ibutamoren (MK-677) were added on September 29, 2023 and remain in Category 2 on the FDA page current as of April 22, 2026. BPC-157, CJC-1295, ipamorelin, AOD-9604, dihexa, DSIP, epitalon, KPV, MOTS-c, selank, semax, melanotan II, LL-37, thymosin alpha-1, and thymosin beta-4 fragment (TB-500) were also placed in Category 2 under the 503A interim policy; that same page now lists them as nominated but withdrawn (see the April 2026 event). Hexarelin, PNC-27, and 5-amino-1MQ have never appeared on the FDA category lists.

   Regulatory: Not eligible for compoundingSource: FDA: Certain bulk drug substances for use in compounding may present significant safety risks (503A and 503B Category 2 lists and withdrawn nominations, content current as of April 22, 2026)

Full tracker for MOTS-c or the category-wide tracker.

What published studies of MOTS-c used

Ranges below are reported from published studies and labeling only. PeptideAgent does not recommend doses or protocols.

Not established in human literature. Mouse studies used 0.5 mg/kg per day intraperitoneally (metabolic studies) and up to 15 mg/kg (exercise studies). No human dose finding or pharmacokinetic study has been published.

Routes reported

MOTS-c side effects

Side effects

Interactions

Contraindications

How do people access MOTS-c legally?

Typical cost: No lawful compounded price: MOTS-c is not on the 503A bulks list, and PCAC's July 2026 recommendation is advisory until FDA publishes a final rule. Advertised clinic prices are not a comparable price. Products sold as research chemicals are not lawful for human use and are not verified for identity or purity.

• MOTS-c cost by channel
• Rules by state
• Verified provider directory

Compare MOTS-c

• Epitalon vs MOTS-c
• MOTS-c vs humanin
• MOTS-c vs SS-31 (elamipretide)
• NAD+ vs MOTS-c

What's actually offered, and what that means for you

Licensed compounding pharmacies, clinics, and telehealth prescribers openly offer many unapproved peptides, and prescribers write prescriptions for them. That does not make MOTS-c lawful. FDA's advisory committee recommended MOTS-c for the 503A bulks list in July 2026, but FDA has not published a final rule, so a pharmacy has no federal basis to compound it yet. [4] [5]

Enforcement is uneven. FDA mostly acts through warning letters to compounders and online sellers, Category 2 safety listings, and import alerts that let it detain shipments, rather than stopping every pharmacy. State pharmacy boards oversee pharmacies day to day, and their rules differ. [8] [9] [10] [11] [12]

What changes for you

• No FDA review of the product: FDA does not check a compounded drug's safety, effectiveness, or quality before it is sold. [12]
• Identity, purity, sterility, and dose accuracy can vary from batch to batch. [10]
• Insurance rarely covers it, so you usually pay cash.
• For tested athletes, MOTS-c is prohibited at all times on the WADA list, whatever the source. [6]

What to check

These checks lower some risks, but they do not make an unlawfully compounded product lawful or safe. Check for:

• A 503A pharmacy licensed in your state (your state board of pharmacy publishes license lookups). [12]
• A real evaluation by a licensed prescriber, not just an online form.
• A certificate of analysis for the specific batch.

Frequently asked questions

Decisions about starting, stopping, or combining any treatment belong with a licensed clinician who knows your history.

From the blog

• MOTS-c for weight loss: what mouse and human studies show

  MOTS-c prevented diet-induced obesity in mice, but no human trial has tested it for weight loss. What the mouse data show, what human blood studies found, and where it stands legally.

• Peptide stacks: what each common component has shown alone

  No trial has tested a multi-peptide stack for muscle growth or fat loss. Nine common stack components ranked by their own human evidence, legal status, and WADA status. No protocols.

• How to read a peptide study

  A practical checklist for judging peptide research: who was studied, how it was designed, what was measured, and whether it was replicated. Worked through with real studies.

• PCAC recommended six peptides. What changes and what does not

  FDA's compounding advisory committee backed BPC-157, KPV, TB-500, MOTS-c, semax, and epitalon for the 503A bulks list and rejected DSIP. Here is what the vote does and does not do.

Sources

Numbered citations above point to these primary sources. PubMed entries link to the indexed abstract.