MOTS-c

MOTS-c is a small peptide encoded by mitochondrial DNA, studied as an 'exercise mimetic' for its effects on metabolism and insulin sensitivity. It acts as a hormone-like signal that activates AMPK, a cellular energy sensor, and is given as an injection under the skin. It is not FDA-approved and is sold only as a research peptide — most evidence is in animals, and no completed human trial has established real-world effectiveness or a standard dose.

MOTS-c has been studied for metabolism and exercise effects. In animal models it improved insulin sensitivity and protected against high-fat-diet-induced obesity, and its natural levels rise with exercise; it is a mitochondrial-derived peptide first characterized in 2015. No completed human Phase 2 or Phase 3 trial has established efficacy or a standardized dose, so the human evidence base is limited.

Not FDA approved for any indication. Research-community use only. Available as a research peptide. ⚠️ WADA-banned in regulated sport — MOTS-c is explicitly named in the WADA 2026 Prohibited List under S4.4.1 (Metabolic Modulators → activators of AMP-activated protein kinase (AMPK)): "…(AMPK), e.g. …mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)", prohibited at all times — the same subsection as AICAR and GW1516. MOTS-c is named explicitly, not captured by a catch-all. Verified against the archived 2026 list directly. Not DEA-scheduled. Sister compound to SS-31 in the mitochondrial-peptide cluster — but mechanistically distinct (SS-31 stabilizes mitochondrial membranes via cardiolipin binding; MOTS-c is encoded within the mitochondrial genome and acts as a hormone-like signaling molecule activating AMPK). ⚖️ Reviewed by FDA's 503A compounding advisory committee; no determination issued: MOTS-c (free base / acetate) was on the FDA Pharmacy Compounding Advisory Committee (PCAC) agenda for July 23–24, 2026 for possible inclusion on the 503A Bulks List (uses evaluated: obesity and osteoporosis; docket FDA-2025-N-6895), and that meeting took place on July 23, 2026, with separate votes on the free base and the acetate. FDA's pre-meeting briefing document proposed that neither form be included. FDA has published no summary minutes, vote results, or determination from that meeting as of 2026-09-03, and a PCAC recommendation is advisory and non-binding — MOTS-c is not on the 503A Bulks List and is not compoundable under 503A on that basis (as of 2026-09-03).

MOTS-c is not FDA-approved and its effects in humans are not established by controlled trials. It is named on the WADA Prohibited List under metabolic modulators / AMPK activators (S4.4.1), prohibited at all times. VialWise is a research and educational reference, not medical advice — consult a licensed professional.

⚠️ For research and educational purposes only. MOTS-c is not approved by the FDA or any major Western regulatory agency as a pharmaceutical drug for any indication. Information in this entry is informational, not medical advice. Always confirm dose calculations and consult appropriate professional guidance before any protocol decisions.

⚠️ No completed human clinical trials have established standardized dosing for MOTS-c. As of this entry's last-updated date, no completed Phase 2 or Phase 3 RCT has been published establishing efficacy or standardized dose for MOTS-c in any human indication.[¹] A first registered interventional human trial does now exist — NCT07505745, a Phase 2a randomized, double-blind, placebo-controlled study of subcutaneous MOTS-c in adults with prediabetes and overweight/obesity (sponsor Hudson Biotech; recruiting; n=120; primary completion February 2027).[⁴] That trial is ongoing with no published results, so it does not change the statement above: efficacy and dose remain unestablished in humans. A registered trial is evidence that a question is being asked, not evidence of an answer. The dose ranges used in research-community protocols are extrapolated from preclinical animal model studies plus accumulated researcher experience — they should be presented to users as observational, not validated. Researchers should be explicit with themselves about the limited human evidence base when interpreting subjective effects.

⚠️ Mechanism — mitochondrial-derived peptide, AMPK activation, and the "exercise mimetic" framing. MOTS-c is encoded within the mitochondrial 12S rRNA gene[¹] — making it one of the first mitochondrial-derived peptides (MDPs) to be characterized as a functional, hormone-like signaling molecule rather than a translation product of a canonical nuclear gene. The compound activates AMP-activated protein kinase (AMPK), the cellular "master energy sensor" — AMPK activation shifts metabolism toward fat oxidation, glucose uptake, and stress-protective responses. In animal models, MOTS-c levels rise in response to exercise, and exogenous MOTS-c administration produces some of the metabolic benefits (insulin sensitivity, glucose handling, fatty acid oxidation) seen with exercise. This is the mechanistic basis for the "exercise mimetic" framing — but the framing should be read as the directional metabolic-signaling claim, not as evidence that MOTS-c can substitute for actual exercise.

⚠️ Precision matters at low doses. MOTS-c is dosed in milligrams per dose in research-community protocols (typical subcutaneous) but at typical reconstitution concentrations the draws still land in the small-volume range on a U-100 syringe. Always verify draws against the in-app calculator and double-check the unit count on the syringe before injecting.

⚠️ The compound is part of a newer research class — the mitochondrial-derived peptides — that is rapidly evolving. MOTS-c was first characterized in 2015 by the Lee/Cohen group at USC.[¹] Since then, the broader class of MDPs (Humanin, Small Humanin-like Peptides, MOTS-c, others) has expanded with continuing research interest. The published literature on MOTS-c specifically continues to accumulate; researchers should expect the evidence base and clinical positioning to evolve over the coming years as more clinical work emerges.

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded within a short open reading frame inside the mitochondrial 12S rRNA gene. The peptide was first characterized in 2015 by the Pinchas Cohen / Changhan David Lee laboratory at the University of Southern California, with the foundational paper published in *Cell Metabolism* describing the peptide's structure, expression patterns, and metabolic effects.[¹] The discovery was significant for two reasons: (1) it demonstrated that the mitochondrial genome harbors functional protein-coding capacity beyond the canonical 13 inner-membrane proteins that had been recognized for decades, and (2) it identified MOTS-c as a hormone-like signaling molecule that links mitochondrial state to cellular and systemic metabolism.

Mechanism — AMPK activation and metabolic signaling. MOTS-c's principal characterized mechanism is activation of AMP-activated protein kinase (AMPK), the cellular "master energy sensor".[¹] AMPK activation produces a coordinated metabolic response: increased fatty acid oxidation, increased glucose uptake into skeletal muscle, decreased anabolic processes (gluconeogenesis, lipogenesis), and activation of stress-protective signaling (autophagy, antioxidant defense). In animal models, exogenous MOTS-c administration recapitulates some of these effects, including improved insulin sensitivity, prevention of high-fat-diet-induced obesity, and protection against age-related metabolic decline.

The "exercise mimetic" framing. MOTS-c blood and skeletal muscle levels rise in response to exercise in human studies — making MOTS-c a potential biomarker of exercise-induced mitochondrial signaling and a candidate for "exercise mimetic" pharmacological intervention. The exercise mimetic framing should be read as directional rather than literal: MOTS-c administration recapitulates some of the metabolic signaling that exercise produces, but does not substitute for the broader physiological adaptations (cardiovascular, neurological, musculoskeletal) that exercise drives. Researchers using MOTS-c on exercise-mimetic rationale should not interpret it as a substitute for actual training.

Mitochondrial-derived peptide (MDP) class. MOTS-c is one of several mitochondrial-derived peptides characterized to date — others include Humanin (encoded in the 16S mitochondrial rRNA gene; neuroprotective and metabolic effects) and the SHLP family (Small Humanin-like Peptides). The MDP class is a rapidly evolving area of research; MOTS-c is currently the most-studied MDP for metabolic/exercise applications.

Common research interests. MOTS-c's research-community use spans: - Insulin sensitivity / metabolic support — the dominant rationale, paralleling the preclinical AMPK-activation and insulin-sensitization findings.[¹] Often used alongside or as adjunct to dietary and exercise interventions. - Exercise tolerance and recovery — research-community use for athletes and active researchers on the rationale of supporting mitochondrial signaling pathways disrupted during intense training. - Longevity / "anti-aging" protocols — research-community use as a longevity intervention; mechanistically aligned with AMPK-activating interventions (metformin, exercise, caloric restriction) that have aging-modifying signal in animal models. - Stack with SS-31 for "mitochondrial cluster" protocols — the canonical pairing in research-community longevity protocols. Mechanism rationale: SS-31 stabilizes mitochondrial membranes; MOTS-c activates AMPK and supports mitochondrial-derived signaling. Together they target two distinct aspects of mitochondrial function. - Type 2 diabetes and metabolic syndrome (research-community use, off-label) — research-community use on the insulin-sensitization rationale; not validated in published RCTs.

Regulatory status. MOTS-c is sold as a research peptide. Not FDA-approved. Not on the FDA 503A bulks list as either Category 1 or Category 2 — its US regulatory status is governed by general 503A requirements rather than a peptide-specific designation. ⚖️ 503A review is active and unresolved. MOTS-c (free base) / MOTS-c acetate was placed on the agenda of the FDA Pharmacy Compounding Advisory Committee (PCAC) meeting of July 23–24, 2026 for possible inclusion on the 503A Bulks List, with the uses evaluated by FDA listed as obesity and osteoporosis (docket FDA-2025-N-6895).[⁵] FDA's published briefing document for the meeting leans against recommending inclusion, citing insufficient human effectiveness and safety evidence along with characterization and immunogenicity concerns — but the committee has not voted and FDA has not issued a final determination, so the outcome should be treated as pending rather than decided. Researchers should confirm the current status against FDA's own docket rather than relying on this entry's snapshot. ⚠️ MOTS-c IS listed in the WADA 2026 Prohibited List under S4.4.1 (Metabolic Modulators → activators of AMP-activated protein kinase (AMPK))[³] — named explicitly ("…(AMPK), e.g. …mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)"), the same subsection as AICAR and GW1516, prohibited at all times. Confirmed directly against the archived 2026 list. Researchers competing in WADA-tested sport should treat MOTS-c as prohibited and confirm against the most recent annual Prohibited List edition before any competitive event.

Commonly reported

• Injection site reactions (uncommon)
• Mild GI symptoms (uncommon)
• Occasional mild fatigue or "off" feeling within hours of dosing — reported infrequently; mechanism unclear
• No consistent pattern of serious adverse events in research-community reports
• Hypoglycemia risk in researchers managing type 2 diabetes — the AMPK-mediated glucose uptake is theoretically additive to insulin or insulin-secretagogue effects.
• Long-term safety in humans is essentially unknown. No multi-year human safety dataset exists.
• Effects on endogenous mitochondrial signaling pathways — the long-term consequences of exogenous MOTS-c administration on endogenous MOTS-c production and mitochondrial signaling are not characterized.
• Pregnancy and lactation safety — no data; default to contraindicated.

Pregnancy and lactation: no data; default to contraindicated

Pediatric use: no data — should not be used in researchers under 18

Active type 1 or type 2 diabetes managed with insulin or insulin-secretagogues — caution; theoretical additive hypoglycemia risk

Active cancer or undiagnosed malignancy concern — limited characterization; the AMPK activation pathway has complex relationships with cancer cell metabolism

Known peptide allergy or hypersensitivity — contraindicated

Regulatory note (US): MOTS-c is sold as a research peptide; not on the FDA 503A bulks list. ⚖️ Under review: MOTS-c was on the FDA Pharmacy Compounding Advisory Committee agenda for July 23–24, 2026, and that meeting took place and the committee voted (uses evaluated: obesity and osteoporosis; docket FDA-2025-N-6895) — committee vote and FDA determination pending as of this update.[⁵]

Regulatory note (WADA): ⚠️ MOTS-c IS listed in the 2026 WADA Prohibited List under S4.4.1 (Metabolic Modulators → AMPK activators), prohibited at all times.[³] Researchers competing in WADA-tested sport should treat MOTS-c as prohibited and confirm against the most recent edition before any competitive event.

Peptide

A short chain of amino acids, the building blocks of proteins. Many compounds in this library are peptides.

Mitochondrial-derived peptide

A peptide encoded within the mitochondrial genome that can act as a hormone-like signal.

AMPK

A cellular "master energy sensor" enzyme; when activated, it shifts metabolism toward burning fat and taking up glucose, mimicking some effects of exercise or fasting.

Subcutaneous

An injection into the fatty layer just under the skin, rather than into a muscle or vein.

WADA Prohibited List

The list of substances banned in regulated sport by the World Anti-Doping Agency.

1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3):443-454. doi: 10.1016/j.cmet.2015.02.009.(PMID 25738459)
2. Zheng Y, Wei Z, Wang T. (2023). MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology, 14:1120533. doi: 10.3389/fendo.2023.1120533.(PMID 36761202)
3. World Anti-Doping Agency. The 2026 Prohibited List, International Standard (effective 1 January 2026). Canonical PDF: wada-ama.org/sites/default/files/2025-09/2026list_en_final_clean_september_2025.pdf (local archival copy in `docs/legal/wada-2026-prohibited-list.pdf`). MOTS-c IS listed in the 2026 WADA Prohibited List under S4.4.1 (Metabolic Modulators → activators of AMP-activated protein kinase (AMPK)), named explicitly alongside AICAR and GW1516, prohibited at all times.
4. ClinicalTrials.gov. A Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of MOTS-c (a Mitochondrial-Derived Peptide) in Adults With Prediabetes and Overweight/Obesity. Registry identifier: NCT07505745. Sponsor: Hudson Biotech. Phase 2 · status recruiting · n=120 · subcutaneous injection · study start 2026-02-02 · primary completion 2027-02-14 · 1 site. The first registered interventional trial administering exogenous MOTS-c to humans — it resolves this entry's long-standing "search for registered human trials" pending marker. ⚠️ Framing discipline: the trial is registered and ongoing with no published results; it is cited here as evidence that a controlled human question is being asked, never as evidence of benefit. The entry's "no completed human RCT, no established efficacy or dose" position is unchanged.(NCT07505745)
5. U.S. Food and Drug Administration. Pharmacy Compounding Advisory Committee (PCAC) meeting, July 23–24, 2026 — docket FDA-2025-N-6895. FDA briefing document: fda.gov/media/193347/download. MOTS-c (free base) / MOTS-c acetate appears on the July 23, 2026 agenda for consideration for the 503A Bulks List; uses evaluated per FDA = obesity and osteoporosis. FDA's briefing document leans against recommending inclusion (insufficient human effectiveness and safety evidence; characterization and immunogenicity concerns). ⚠️ No determination: the meeting has since taken place and the committee voted, but FDA has published no summary minutes, vote results, or final decision — this entry deliberately reports the review as open, not decided.
6. MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases. Journal of Translational Medicine, 2026.(PMID 42243958)

• SS-31 — discussed together in this entry's stacks section
• Humanin — same mechanism class
• Adipotide — shared research area
• Amycretin — shared research area
• AOD-9604 — shared research area
• Cagrilintide — shared research area