MOTS-C for Research in Canada

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide, MRWQEMGYIFYPRKLR, whose gene sits inside the mitochondrial genome rather than the nuclear one. Lee and colleagues reported it in 2015 as a second mitochondrial-encoded signalling peptide after humanin, showing that it activates AMPK by inhibiting the folate cycle and de-novo purine synthesis, and that treating mice with it prevented age-related and high-fat-diet-induced insulin resistance^[1]. Since then it has been studied as a “mitochondrial-derived peptide” in mouse muscle and metabolism models, in cultured myotubes, and in human cohorts where only the body’s own MOTS-c was measured^{[3, 4]}. No approved product exists, and we found no interventional human trial of the synthetic peptide. The vials and pen on this page are supplied for laboratory research only.

Key facts

• Origin: encoded by a short open reading frame within the mitochondrial 12S ribosomal RNA gene; described in 2015^[1].
• Size: 16 residues, C₁₀₁H₁₅₂N₂₈O₂₂S₂, 2174.6 g/mol (PubChem).
• Mechanism studied: AMPK activation via the folate–purine axis^[1]; under metabolic stress the peptide moves into the nucleus and regulates genes carrying antioxidant response elements, interacting with NRF2^[2].
• Models: mice (young, middle-aged, old; high-fat-fed; immobilised), C2C12 myotubes, and observational human data on endogenous plasma and muscle MOTS-c^{[3, 7, 9]}.
• A natural variant matters: the East-Asian mtDNA polymorphism m.1382A>C changes lysine 14 to glutamine (K14Q), a less active form; in a 27,527-person meta-analysis, men with the C allele had a higher prevalence of type 2 diabetes^[5].
• Documentation on this site: no batch report for any MOTS-c listing is posted in the COA library at the time of writing.

Discovery

The mitochondrial genome was long assumed to code only for 13 respiratory-chain proteins plus its own tRNAs and rRNAs. The identification of humanin, a peptide encoded in the 16S rRNA gene, suggested that other short open reading frames might exist. Lee and colleagues searched the 12S rRNA gene and found one encoding a 16-residue peptide they named MOTS-c. In their 2015 paper the peptide’s main target organ appeared to be skeletal muscle; at the cellular level it inhibited the folate cycle and the purine biosynthesis tethered to it, which raised AMP and activated AMPK^[1]. A 2018 follow-up from the same group showed that, under glucose restriction, MOTS-c moves from the cytoplasm into the nucleus in an AMPK-dependent way and there regulates a broad set of genes, including antioxidant-response-element genes, by interacting with stress-responsive transcription factors such as NRF2 — evidence that the mitochondrial genome can talk back to the nuclear one^[2].

Identity

Read from PubChem on 30 September 2026. ChEMBL has no record for MOTS-c under this name, so the identity rests on PubChem and the primary literature.

What researchers have studied, by model

Cell culture

In differentiated C2C12 mouse myotubes, MOTS-c prevented palmitic-acid-induced atrophy; mechanistically it raised CK2 activity, inhibited PTEN, increased mTORC2 signalling and AKT phosphorylation, and so restrained FOXO1, a transcription factor upstream of myostatin^[7]. In cells under glucose restriction it accumulated in the nucleus and altered gene expression^[2]; myoblasts adapted differently to metabolic stress in its presence^[3]. The K14Q variant showed diminished insulin-sensitising activity in vitro^[5].

Mouse

The discovery paper reported that MOTS-c treatment prevented diet-induced obesity and both age-dependent and high-fat-diet-induced insulin resistance^[1]. In 2021, Reynolds and colleagues found that the peptide enhanced physical performance in young (2-month), middle-aged (12-month) and old (22-month) mice, and that intermittent treatment begun late in life (23.5 months) increased physical capacity and healthspan; it regulated nuclear genes for metabolism and proteostasis and altered skeletal-muscle metabolism^[3]. High-fat-fed male mice given wild-type MOTS-c showed lower weight and better glucose tolerance, whereas the K14Q form did not; females were unaffected^[5]. In diet-induced obese mice, MOTS-c lowered plasma myostatin^[7]. In a 2022 exercise study, 4–8 weeks of voluntary running raised muscle MOTS-c protein 1.5- to 5-fold, an effect that persisted through 4–6 weeks of detraining, and a single administration to untrained mice improved running time and distance in an acute test by 12% and 15%^[8]. In 2024, mice with a cast-immobilised limb lost about 15% of muscle mass over eight days, versus about 5% with MOTS-c, alongside normalised AKT/FOXO signalling, lower circulating IL-6, IL-1β, CXCL1 and MCP-1, and less intramuscular fat^[9]. Injecting a MOTS-c-neutralising antibody shifted muscle toward fast myosin heavy chain, mimicking the K14Q genotype^[6].

Human (endogenous MOTS-c only)

Nobody has published a trial giving synthetic MOTS-c to people. What exists is measurement of the body’s own peptide. Exercise induces MOTS-c expression in human skeletal muscle and raises it in circulation^[3]. In ten lean and ten obese adults, plasma MOTS-c was similar between groups (about 0.5 ng/mL) but correlated with insulin-resistance indices, mainly in the lean group^[4]. In 49 breast-cancer survivors, a 16-week aerobic-plus-resistance programme raised plasma MOTS-c in non-Hispanic White but not Hispanic participants, and the post-exercise level tracked reductions in fat mass, weight, HOMA-IR and CRP^[10]. Plasma MOTS-c was inversely correlated with myostatin in human subjects^[7]. On the genetic side, the K14Q variant was associated with type 2 diabetes prevalence in men (three cohorts, n = 27,527), particularly the least active tertile^[5], and with a higher share of fast-twitch MHC-IIx fibres, higher leg torque and a higher frequency among sprint/power athletes in Japanese cohorts^[6]. Reviews note that plasma levels decline with age and that no clinical method of using MOTS-c has been developed^{[11, 12]}.

Study summary

What the evidence does not show

• No trial has given synthetic MOTS-c to humans; every human data point above is a measurement of the endogenous peptide or of a gene variant^{[4, 10, 5]}. Nothing here supports any effect of the vial on people.
• Mouse findings are sex-specific in at least one study (females unaffected)^[5] and strain- and model-specific in others; the ageing work is from one group^[3].
• The plasma study that found MOTS-c tracking insulin resistance had ten people per group^[4], and the exercise study was a secondary analysis of a cancer-survivor trial^[10].
• Reviews written in 2022–2023 state plainly that no effective clinical method of applying MOTS-c has been developed^{[11, 12]}.
• No MOTS-c listing on this site has a posted batch report yet; the label values are declared, not measured.

Handling and storage for laboratory use

• Lyophilized powder in sealed vials (or a pre-filled pen cartridge, see below): cool, dry and dark for short periods; −20 °C for long-term storage per the site’s guidance; avoid repeated freeze–thaw.
• Water-soluble; the 2024 immobilisation study used sterilised water as its injection vehicle^[9]. Reconstituted solutions are less stable than powder. Bacteriostatic water is listed separately.

References

1. Lee C, Zeng J, Drew BG et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell metabolism 21(3):443-54. doi:10.1016/j.cmet.2015.02.009. PMID 25738459
2. Kim KH, Son JM, Benayoun BA et al. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell metabolism 28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008. PMID 29983246
3. Reynolds JC, Lai RW, Woodhead JST et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature communications 12(1):470. doi:10.1038/s41467-020-20790-0. PMID 33473109
4. Cataldo LR, Fernández-Verdejo R, Santos JL et al. (2018). Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 66(6):1019-1022. doi:10.1136/jim-2017-000681. PMID 29593067
5. Zempo H, Kim SJ, Fuku N et al. (2021). A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging 13(2):1692-1717. doi:10.18632/aging.202529. PMID 33468709
6. Kumagai H, Natsume T, Kim SJ et al. (2022). The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochimica et biophysica acta. General subjects 1866(2):130048. doi:10.1016/j.bbagen.2021.130048. PMID 34728329
7. Kumagai H, Coelho AR, Wan J et al. (2021). MOTS-c reduces myostatin and muscle atrophy signaling. American journal of physiology. Endocrinology and metabolism 320(4):E680-E690. doi:10.1152/ajpendo.00275.2020. PMID 33554779
8. Hyatt JK (2022). MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiological reports 10(13):e15377. doi:10.14814/phy2.15377. PMID 35808870
9. Kumagai H, Kim SJ, Miller B et al. (2024). Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration. American journal of physiology. Endocrinology and metabolism 326(3):E207-E214. doi:10.1152/ajpendo.00285.2023. PMID 38170165
10. Dieli-Conwright CM, Sami N, Norris MK et al. (2021). Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors. Scientific reports 11(1):16916. doi:10.1038/s41598-021-96419-z. PMID 34413391
11. 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
12. Mohtashami Z, Singh MK, Salimiaghdam N et al. (2022). MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International journal of molecular sciences 23(19). doi:10.3390/ijms231911991. PMID 36233287