MOTS-c

What it is

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide that is unusual among signaling molecules because it is encoded directly in mitochondrial DNA, within the 12S rRNA gene, rather than in the nuclear genome. Discovered by Lee and colleagues in 2015, MOTS-c activates AMPK and influences glucose and lipid metabolism, and it is sometimes called an 'exercise mimetic' because human studies show that circulating and skeletal-muscle MOTS-c rise with acute exercise and that circulating levels decline with age. It is investigational and is not approved by the FDA or any regulator for any use; no drug label exists. Essentially all evidence that injected MOTS-c improves insulin sensitivity, obesity, or physical performance comes from mouse experiments using intraperitoneal doses of 5 to 15 mg/kg; no peer-reviewed human trial of native MOTS-c has yet reported results. A related synthetic analog, CB4211, completed Phase 1 human safety testing, and a separate Phase 2a trial of native MOTS-c in people with prediabetes is currently recruiting, but neither has published outcomes. Human-injectable dosing protocols circulating online come entirely from vendors and community reports, not clinical studies. Readers should treat MOTS-c as an early-stage research compound: its endogenous biology in humans is genuinely documented, but functional dosing evidence remains preclinical, animal-only. On the regulatory side, MOTS-c was removed from the FDA's restricted Category 2 compounding list in April 2026 and was one of six peptides an FDA advisory committee voted in July 2026 to recommend for the Section 503A Bulks List; that recommendation is nonbinding and does not make MOTS-c an approved drug or, by itself, legal to compound, and it adds no human efficacy evidence. See our peptide regulation tracker for the dated detail.

Dose ranges

Study-backed ranges carry a source you can open. Community ranges are widely reported but not clinically established - treat them as what people do, not as advice.

Reconstitution & storage

Community and vendor sources most commonly describe 5 mg or 10 mg lyophilized vials reconstituted with 1-3 mL bacteriostatic water (for example, 10 mg plus 2 mL yields roughly 5 mg/mL). No manufacturer or clinical reconstitution protocol exists because no MOTS-c drug product is FDA-approved or has a DailyMed label; these figures reflect unregulated community and compounding practice only, not a validated standard.

Interactions & cautions

No peer-reviewed human drug-interaction studies exist for MOTS-c, since it has not completed a published human efficacy trial. Mechanistically, MOTS-c activates AMPK and increases insulin sensitivity in mouse studies (Lee et al. 2015), which is the biological basis for a theoretical, community-flagged concern that combining MOTS-c with insulin or insulin secretagogues (e.g., sulfonylureas) could compound glucose-lowering effects; this concern comes from community/vendor sources, not from a clinical interaction study, and has not been tested in humans. A related synthetic analog, CB4211, completed a Phase 1 safety/tolerability trial (NCT03998514) with no adverse-event results posted publicly as of this writing, and a Phase 2a trial of native MOTS-c (NCT07505745) is recruiting but has not reported safety data. Community and vendor sources additionally flag a theoretical caution about combining MOTS-c with metformin, since both activate AMPK, and suggest starting at a lower dose; like the insulin caution, this is community-level and not established in any human study.

Questions people ask

Sources

1. [1]The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (Lee et al., Cell Metabolism 2015) PMID 25738459studyDiscovery and identity of the 16-amino-acid MOTS-c peptide encoded in mtDNA 12S rRNA; mouse data showing MOTS-c prevents age- and diet-induced insulin resistance and diet-induced obesity via AMPK activation.
2. [2]A mitochondrially encoded hormone ameliorates obesity and insulin resistance (Zarse & Ristow, preview commentary, Cell Metabolism 2015) PMID 25738453reviewIndependent commentary summarizing the Lee et al. 2015 discovery and the AICAR/AMPK mechanism proposed for MOTS-c.
3. [3]MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (Reynolds et al., Nature Communications 2021) PMID 33473109studyHuman exercise data (skeletal-muscle MOTS-c up 11.9-fold, circulating MOTS-c up 1.5-1.6-fold, returning to baseline by 4 hours); mouse dosing (5 or 15 mg/kg intraperitoneal) and late-life intermittent treatment improving physical capacity and showing a modest lifespan trend in mice.
4. [4]Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition (Aging, Albany NY, 2020) PMID 32182209studyHuman data: circulating plasma MOTS-c declines with age while skeletal-muscle MOTS-c expression is about 1.5-fold higher in older and middle-aged men versus young men; correlates with myofiber composition and muscle quality.
5. [5]A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c (Zempo et al., Aging, Albany NY, 2021) PMID 33468709studyLarge human cohort meta-analysis (n=27,527) linking the MOTS-c m.1382A>C (K14Q) variant to type 2 diabetes risk in sedentary men; companion mouse data showing native MOTS-c, but not the K14Q variant, improves glucose metabolism.
6. [6]Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss (Journal of Clinical & Translational Endocrinology, 2025) PMID 41551324studyHuman cohort data (22 lean vs 32 obese adults) showing circulating MOTS-c is higher in obesity (273 vs 223 pg/mL, p<0.01) and does not change after bariatric-surgery weight loss, suggesting a compensatory metabolic response rather than a simple deficiency state.
7. [7]MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation (Frontiers in Endocrinology review, 2023)reviewStates that, as of publication, no effective clinical method of applying MOTS-c had been developed and no completed human efficacy trials existed; summarizes mechanistic and preclinical translational status.
8. [8]PubChem Compound Summary for CID 146675088, MOTS-creferenceConfirms MOTS-c chemical identity: 16-residue sequence Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR), molecular formula C101H152N28O22S2, molecular weight approximately 2174.6 g/mol.
9. [9]DailyMed search results for "MOTS-c"regulatoryConfirms zero FDA drug labels exist for MOTS-c, i.e., it is not an FDA-approved or labeled drug product.
10. [10]ClinicalTrials.gov NCT03998514: A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver DiseaseregulatoryRegistry record for a completed Phase 1 subcutaneous dose-escalation trial of CB4211, a synthetic MOTS-c analog (not native MOTS-c), in 88 participants; no results posted on the registry as of this writing.
11. [11]ClinicalTrials.gov NCT07505745: MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/ObesityregulatoryRegistry record for an ongoing/recruiting Phase 2a trial of native MOTS-c by subcutaneous injection over 12 weeks in adults with prediabetes and overweight/obesity, primary endpoint the Matsuda insulin-sensitivity index; no results posted yet.
12. [12]MOTS-C Dosage Chart: Protocol Guide for Metabolic Health & Performance (Healthspan, community/vendor article)communityCommunity/vendor-reported dosing titration patterns, bacteriostatic-water reconstitution, and roughly 30-day refrigerated stability claims, with an explicit disclaimer that no universally accepted clinical dosing standard for MOTS-c exists; the page also carries community-level cautions about additive glucose-lowering with insulin and additive AMPK activation with metformin.
13. [13]MOTS-c Dosage: Protocols & Timing (PeptidesExplorer, community/vendor article)communityCommunity/vendor-reported typical vial size (10 mg), reconstitution ratios, weekly dosing and cycling patterns, storage practices, and anecdotal side-effect and hypoglycemia-risk reports for injectable MOTS-c.
14. [14]FDA advisory committee nominates six peptides for pharmacies to compound (NCPA, 2026)regulatoryReports that on July 23-24, 2026 the FDA Pharmacy Compounding Advisory Committee recommended six of seven reviewed peptides (including MOTS-c) for the 503A Bulks List, that the recommendation is nonbinding, that the HHS Secretary must formally approve, and that pharmacies may not compound them until final rulemaking is in place; the basis for the 2026 regulatory-status note and FAQ.