MOTS-c

1. Studied for

   Genetics: the K14Q mitochondrial variant

   A single-letter change in mitochondrial DNA, found specifically in Asian populations, swaps a single amino acid in MOTS-c and produces a version called K14Q. Pooling 3 large Japanese and Japanese-ancestry cohorts totaling 27,527 people, researchers reported that men carrying that change had a higher prevalence of type 2 diabetes, while women did not. In 1 of the 3 cohorts, the raised prevalence appeared only in the men who were least physically active, which the authors describe as a gene-by-exercise interaction. In mice on a high-fat diet, males given normal MOTS-c showed reduced weight and improved glucose tolerance while males given the K14Q version did not, and female mice were unaffected either way. In cell experiments, the K14Q version was worse at making cells insulin-sensitive. Human population genetics, animal work and cell work point the same direction here, which is why this is the strongest-supported entry on this page. human population genetics (27,527 people across 3 cohorts), plus mouse studies and cultured cells Preclinical strong Convergent results from more than one independent laboratory across more than one experimental system. Still preclinical: 'strong' here never means clinical-grade evidence in people. Open for the full finding and the paper it came from.

   In the literature

   Genetics: the K14Q mitochondrial variant

   A single-letter change in mitochondrial DNA, found specifically in Asian populations, swaps a single amino acid in MOTS-c and produces a version called K14Q. Pooling 3 large Japanese and Japanese-ancestry cohorts totaling 27,527 people, researchers reported that men carrying that change had a higher prevalence of type 2 diabetes, while women did not. In 1 of the 3 cohorts, the raised prevalence appeared only in the men who were least physically active, which the authors describe as a gene-by-exercise interaction. In mice on a high-fat diet, males given normal MOTS-c showed reduced weight and improved glucose tolerance while males given the K14Q version did not, and female mice were unaffected either way. In cell experiments, the K14Q version was worse at making cells insulin-sensitive. Human population genetics, animal work and cell work point the same direction here, which is why this is the strongest-supported entry on this page.^{References 1}

   Modelhuman population genetics (27,527 people across 3 cohorts), plus mouse studies and cultured cells

   Confidence: strong

   Convergent results from more than one independent laboratory across more than one experimental system. Still preclinical: 'strong' here never means clinical-grade evidence in people.

   Source

   Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. doi:10.18632/aging.202529. PMID: 33468709

   PubMed 33468709

   How this citation was checked

   Resolved from both ends by the verification pass in research/clean/mots-c.json and not re-resolved in this derivation. Crossref returned this exact title, first author Zempo Hirofumi with Kim Su-Jeong and Fuku Noriyuki as authors 2 and 3 (matching the 'Zempo H, Kim SJ, Fuku N, et al.' form), Aging volume 13 issue 2, pages 1692-1717, issued 2021-01-19, 29 authors. PubMed efetch of PMID 33468709 returned the identical title and page range. Phrases taken verbatim from that abstract: 'an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement'; 'males but not females with the C-allele exhibit a higher prevalence of T2D'; 'In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D'; 'Like the human data, female mice were unaffected'; and 'K14Q-MOTS-c leads to diminished insulin-sensitization in vitro'. This is the only 'strong' badge on the page and it rests on a single publication, so what earns it is stated rather than assumed: 3 independently assembled cohorts meta-analyzed, plus a mouse arm and an in vitro arm, all pointing one way. Author affiliations were not resolved in the verification pass, so laboratory independence in the sense the legend uses is not separately established. On disease naming: type 2 diabetes is named in this finding as a population outcome associated with an inherited variant of the peptide, never as something this compound acts on, prevents or is for, and no statement of that second kind appears anywhere on this page.

2. Studied for

   Glucose handling and insulin signaling (discovery paper)

   The paper that first identified MOTS-c reported that, in mice, giving the peptide prevented the loss of insulin sensitivity that normally comes with age and with a high-fat diet, and prevented the weight gain that diet caused. In cultured cells, the authors traced this to the peptide blocking a metabolic route called the folate cycle and the purine-building pathway attached to it, which switches on an energy-sensing enzyme called AMPK. Skeletal muscle appeared to be the main tissue affected; the abstract's own wording is that its primary target organ appears to be the skeletal muscle. This is a single mouse-and-cell-culture study, not a study in people. in cultured cells and in mouse studies Preclinical moderate A well-described result with several independent outcome measures, but from a single laboratory or a single study design. Open for the full finding and the paper it came from.

   In the literature

   Glucose handling and insulin signaling (discovery paper)

   The paper that first identified MOTS-c reported that, in mice, giving the peptide prevented the loss of insulin sensitivity that normally comes with age and with a high-fat diet, and prevented the weight gain that diet caused. In cultured cells, the authors traced this to the peptide blocking a metabolic route called the folate cycle and the purine-building pathway attached to it, which switches on an energy-sensing enzyme called AMPK. Skeletal muscle appeared to be the main tissue affected; the abstract's own wording is that its primary target organ appears to be the skeletal muscle. This is a single mouse-and-cell-culture study, not a study in people.^{References 2}

   Modelin cultured cells and in mouse studies

   Confidence: moderate

   A well-described result with several independent outcome measures, but from a single laboratory or a single study design.

   Source

   Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. doi:10.1016/j.cmet.2015.02.009. PMID: 25738459

   PubMed 25738459

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the title 'The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance', first author Lee Changhan, Cell Metabolism volume 21 issue 3, pages 443-454, issued 2015-03, 11 authors. PubMed efetch of PMID 25738459 returned the same record with a matching DOI. The abstract states verbatim 'a 16-amino-acid peptide named MOTS-c', 'Its primary target organ appears to be the skeletal muscle' and 'inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation'. Full text was read through PMC4350682, a PMCID obtained from the NCBI ID converter rather than guessed. Confidence is capped at moderate because it is a single study from a single group. The animal figures printed in that paper are deliberately not reproduced here.

3. Studied for

   Exercise response and age-related physical decline

   In people, a single bout of exercise raised the body's own MOTS-c in muscle tissue (11.9-fold above each person's pre-exercise value) and in the bloodstream (1.6-fold during exercise and 1.5-fold after), with blood levels returning to baseline after 4 hours of rest. In mice, giving the peptide improved physical performance at young (2 months), middle (12 months) and old (22 months) ages; in the old animals specifically, mice given MOTS-c ran 2-fold longer and 2.16-fold farther than control animals. Grip strength was not improved in young mice. Grip strength, stride length and walking performance did improve in a separate arm where the peptide was first given late in life. The striking running results are mouse results. Nothing comparable was tested in people: the human part of this study measured the body's own peptide around exercise and gave the participants nothing. in mouse studies (young, middle-aged and aged), plus muscle biopsy and blood sampling in human volunteers Preclinical moderate A well-described result with several independent outcome measures, but from a single laboratory or a single study design. Open for the full finding and the paper it came from.

   In the literature

   Exercise response and age-related physical decline

   In people, a single bout of exercise raised the body's own MOTS-c in muscle tissue (11.9-fold above each person's pre-exercise value) and in the bloodstream (1.6-fold during exercise and 1.5-fold after), with blood levels returning to baseline after 4 hours of rest. In mice, giving the peptide improved physical performance at young (2 months), middle (12 months) and old (22 months) ages; in the old animals specifically, mice given MOTS-c ran 2-fold longer and 2.16-fold farther than control animals. Grip strength was not improved in young mice. Grip strength, stride length and walking performance did improve in a separate arm where the peptide was first given late in life. The striking running results are mouse results. Nothing comparable was tested in people: the human part of this study measured the body's own peptide around exercise and gave the participants nothing.^{References 3}

   Modelin mouse studies (young, middle-aged and aged), plus muscle biopsy and blood sampling in human volunteers

   Confidence: moderate

   A well-described result with several independent outcome measures, but from a single laboratory or a single study design.

   Source

   Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. doi:10.1038/s41467-020-20790-0. PMID: 33473109

   PubMed 33473109

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the exact title, first author Reynolds Joseph C., Nature Communications volume 12 issue 1, article 470, issued 2021-01-20, 12 authors. PubMed efetch of PMID 33473109 returned the same record and DOI, and its abstract confirms the 2, 12 and 22 month cohorts and that exercise induces the body's own MOTS-c in human skeletal muscle and circulation. Every figure quoted above was read from the full text through PMC7817689, a PMCID obtained from the NCBI ID converter: '(11.9-fold)', 'during (1.6-fold) and after (1.5-fold) exercise', 'Old mice ran longer (2-fold; Fig. 3c) and farther (2.16-fold; Fig. 3d)', 'but not grip strength (Supplementary Fig. 2b) in young mice', and the late-life arm improving grip strength, stride length and a 60-second walking test. A further result from this paper, a treadmill sprint-stage contrast between 2 groups on different concentrations, is deliberately not carried; see verification.omitted_claims.

4. Studied for

   Mechanism: a signal sent from the mitochondria to the cell nucleus

   In cultured human cells under metabolic stress, MOTS-c moved out of the mitochondria and into the nucleus, where it changed which genes were switched on, and this depended on the energy-sensing enzyme AMPK. When the cells were starved of glucose, the peptide altered a wide set of genes, including a group governed by a stress-response switch called NRF2, and it interacted with the proteins that control that switch. The authors present this as evidence that the mitochondrial genome and the nuclear genome signal to each other in both directions. This is cell-culture work only, with no animal or human arm, and it reports which genes changed rather than any measured outcome downstream of them. in cultured human cells (HEK293 and HepG2 cell lines) Preclinical preliminary A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference. Open for the full finding and the paper it came from.

   In the literature

   Mechanism: a signal sent from the mitochondria to the cell nucleus

   In cultured human cells under metabolic stress, MOTS-c moved out of the mitochondria and into the nucleus, where it changed which genes were switched on, and this depended on the energy-sensing enzyme AMPK. When the cells were starved of glucose, the peptide altered a wide set of genes, including a group governed by a stress-response switch called NRF2, and it interacted with the proteins that control that switch. The authors present this as evidence that the mitochondrial genome and the nuclear genome signal to each other in both directions. This is cell-culture work only, with no animal or human arm, and it reports which genes changed rather than any measured outcome downstream of them.^{References 4}

   Modelin cultured human cells (HEK293 and HepG2 cell lines)

   Confidence: preliminary

   A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference.

   Source

   Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008. PMID: 29983246

   PubMed 29983246

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the exact title and the 4-author list Kim Kyung Hwa, Son Jyung Mean, Benayoun Berenice A., Lee Changhan, Cell Metabolism 28(3):516-524.e7, issued 2018-09. PubMed efetch of PMID 29983246 returned the identical title, first author and DOI, with a journal PubDate of 2018 Sep 04 confirming the year printed in the citation. The abstract states verbatim the AMPK-dependent nuclear translocation, the glucose restriction, the antioxidant response elements and the NFE2L2/NRF2 interaction. The 2 cell lines are not named in the abstract, so the full text was read through PMC6185997, which names HEK293 as the primary system and HepG2 as the confirmatory one. This paper shares an author with the discovery paper above (Lee C), which is why the 2 are not counted as independent laboratories.

5. Studied for

   Blood MOTS-c and muscle strength in people (an observational correlation)

   In a small group of physically active volunteers who were given nothing, the amount of MOTS-c circulating in the blood at rest tracked with the power and force they produced in a jump test, and with how much muscle they carried overall and in their legs. It did not track with body fat percentage, and it did not track at all with peak oxygen uptake, the treadmill measure of how much oxygen the body can use at maximum effort. This is a correlation observed in people who received nothing, not a test of giving the peptide, and the authors themselves call it a preliminary study. in a human observational study (20 physically active volunteers: 17 male, 3 female, median age 30), no peptide was given Preclinical preliminary A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference. Open for the full finding and the paper it came from.

   In the literature

   Blood MOTS-c and muscle strength in people (an observational correlation)

   In a small group of physically active volunteers who were given nothing, the amount of MOTS-c circulating in the blood at rest tracked with the power and force they produced in a jump test, and with how much muscle they carried overall and in their legs. It did not track with body fat percentage, and it did not track at all with peak oxygen uptake, the treadmill measure of how much oxygen the body can use at maximum effort. This is a correlation observed in people who received nothing, not a test of giving the peptide, and the authors themselves call it a preliminary study.^{References 5}

   Modelin a human observational study (20 physically active volunteers: 17 male, 3 female, median age 30), no peptide was given

   Confidence: preliminary

   A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference.

   Source

   Domin R, Pytka M, Zolynski M, et al. MOTS-c serum concentration positively correlates with lower-body muscle strength and is not related to maximal oxygen uptake-A preliminary study. Int J Mol Sci. 2023;24(19):14951. doi:10.3390/ijms241914951. PMID: 37834399

   PubMed 37834399

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the full published title including its 'A Preliminary Study' suffix, first author Domin Remigiusz, International Journal of Molecular Sciences volume 24 issue 19, article 14951, issued 2023-10-06, 8 authors. PubMed efetch of PMID 37834399 returned the identical title, first author and DOI. The abstract confirms verbatim the 17 male / 3 female / median age 30 cohort, that serum MOTS-c 'was positively correlated with the average power and average and maximal force of the jumps, both overall muscle mass and leg muscle mass, but not with body fat percentage', and 'There was no correlation with peak VO2'. The negative result is carried here as deliberately as the positive one: it is the reason this store does not sell an aerobic-fitness claim on this compound.

6. Studied for

   Blood MOTS-c in trained athletes

   In a pilot comparison of professional athletes against sedentary people matched for age and body size, the athletes had lower blood MOTS-c and higher blood humanin than the sedentary group. Within the athlete groups, MOTS-c did not differ between the sport-type subgroups the authors defined by training demand, although humanin did. MOTS-c and humanin levels tracked closely with each other in athletes but not in sedentary people. The authors describe this as pilot data. The direction is worth stating plainly: years of training went with lower circulating MOTS-c, which sits alongside, rather than confirming, the short-term rises measured after a single bout of exercise. in a human observational pilot study (30 non-athlete controls and 75 professional athletes), no peptide was given Preclinical preliminary A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference. Open for the full finding and the paper it came from.

   In the literature

   Blood MOTS-c in trained athletes

   In a pilot comparison of professional athletes against sedentary people matched for age and body size, the athletes had lower blood MOTS-c and higher blood humanin than the sedentary group. Within the athlete groups, MOTS-c did not differ between the sport-type subgroups the authors defined by training demand, although humanin did. MOTS-c and humanin levels tracked closely with each other in athletes but not in sedentary people. The authors describe this as pilot data. The direction is worth stating plainly: years of training went with lower circulating MOTS-c, which sits alongside, rather than confirming, the short-term rises measured after a single bout of exercise.^{References 6}

   Modelin a human observational pilot study (30 non-athlete controls and 75 professional athletes), no peptide was given

   Confidence: preliminary

   A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference.

   Source

   Alser M, Ramanjaneya M, Anwardeen NR, et al. The effect of chronic endurance exercise on serum levels of MOTS-c and humanin in professional athletes. Rev Cardiovasc Med. 2022;23(5):181. doi:10.31083/j.rcm2305181. PMID: 39077591

   PubMed 39077591

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the exact title, first author Alser Maha, Reviews in Cardiovascular Medicine volume 23 issue 5, article 181, issued 2022-05-18, 10 authors. PubMed efetch of PMID 39077591 returned the identical title, first author and DOI; the 39-prefix PMID on a 2022 paper is retrospective PubMed indexing, and the journal PubDate field confirms the 2022 volume year. The abstract confirms verbatim 'Serum samples were collected from 30 non-athlete controls and 75 professional athletes', 'professional athletes had lower levels of MOTS-c and higher levels of Humanin than sedentary controls', that 'MOTS-c levels did not change between the subgroups', that the 2 peptides 'were highly correlated in athletes, but not in sedentary controls', and 'This pilot data suggests'. The journal's name is a bibliographic fact and carries no cardiovascular claim; this page makes none.

7. Studied for

   Blood MOTS-c and body and liver fat in people

   In people without diabetes, blood MOTS-c and a related mitochondrial peptide called SHLP2 were higher, not lower, in those with metabolic syndrome. Fat carried around the middle raised blood MOTS-c more than total body fat did, and once total fat was accounted for, more fat in the liver went with more MOTS-c in the blood. Both peptides were also higher in people with raised liver damage markers, and higher in male mice fed a diet that loads the liver with fat. The authors propose that a stressed liver is what pushes these peptides up, meaning a high level may be a distress signal rather than a sign of health. That runs opposite to the simple idea that more MOTS-c means better metabolic health, and it is the reason this page makes no claim in that direction. in a human observational study (125 Chinese participants, 91 male and 34 female, plus 34 European Caucasian female participants for imaging), with a supporting male mouse arm; no peptide was given to the human participants Preclinical preliminary A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference. Open for the full finding and the paper it came from.

   In the literature

   Blood MOTS-c and body and liver fat in people

   In people without diabetes, blood MOTS-c and a related mitochondrial peptide called SHLP2 were higher, not lower, in those with metabolic syndrome. Fat carried around the middle raised blood MOTS-c more than total body fat did, and once total fat was accounted for, more fat in the liver went with more MOTS-c in the blood. Both peptides were also higher in people with raised liver damage markers, and higher in male mice fed a diet that loads the liver with fat. The authors propose that a stressed liver is what pushes these peptides up, meaning a high level may be a distress signal rather than a sign of health. That runs opposite to the simple idea that more MOTS-c means better metabolic health, and it is the reason this page makes no claim in that direction.^{References 7}

   Modelin a human observational study (125 Chinese participants, 91 male and 34 female, plus 34 European Caucasian female participants for imaging), with a supporting male mouse arm; no peptide was given to the human participants

   Confidence: preliminary

   A single study, an early mechanistic observation, or a result whose interpretation is the authors' own inference.

   Source

   Sequeira IR, Woodhead JST, Chan A, et al. Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes. Biochim Biophys Acta Gen Subj. 2021;1865(11):129991. doi:10.1016/j.bbagen.2021.129991. PMID: 34419510

   PubMed 34419510

   How this citation was checked

   Resolved from both ends by the verification pass and not re-resolved here. Crossref returned the exact title and the author order Sequeira Ivana R., Woodhead Jonathan S.T., Chan Alex, D'Souza Randall F., Wan Junxiang, Hollingsworth Kieren G. and 4 more, Biochimica et Biophysica Acta General Subjects volume 1865 issue 11, article 129991, issued 2021-11. An earlier draft of that research pass credited a wrong first author (Ramanjaneya M); Crossref and PubMed both return Sequeira IR, and PubMed efetch of PMID 34419510 returned the identical title and DOI. The abstract confirms verbatim the 125 Chinese participants (91 male, 34 female), the additional 34 European Caucasian female participants, that plasma MOTS-c and SHLP2 'were elevated in those with MS', that 'Android fat had a greater effect on increasing plasma MOTS-c (p < 0.004)', that 'liver fat positively associated with plasma MOTS-c and SHLP2', the elevated liver damage markers, the male C57Bl/6j mouse arm, and the authors' hormetic 'hepatic centric' interpretation. Confidence is preliminary, matching the other single human observational studies here: the mouse arm supports the interpretation but does not replicate the human observation.

1 strong / 2 moderate / 4 preliminaryRated by how many independent labs and how many kinds of experiment found the same thing.