Research-only educational guide

MOTS-c Dosage Calculator and Chart

A structured summary of the published literature examining MOTS-c (mitochondrial open-reading-frame of the 12S rRNA-c), including reported dosing concepts, metabolic mechanisms, experimental applications, and safety considerations discussed in research contexts.

MOTS-c Dosage Chart: Quick Breakdown

The chart below summarizes dosing structures described in the provided research guide text as an informational reference only (not a clinical guideline).

Example 20-day research protocol structure described in the guide (informational reference only).
Protocol Timeline Exposure Frequency Notes
Weight loss / metabolism (example) 20 days Four doses of 5–10 mg (subcutaneous) [5,17] Every 5 days [5] Guide text also discusses repeating a second cycle within ~6 months. [5]
Repeat / cycle spacing (example) ~6 months Second identical cycle (discussion) After completing initial 20-day study Presented as a research-summary recommendation. [5]

The guide also notes that animal data have included substantially higher mg/kg dosing discussions, while suggesting potential human-trial experimental doses should be more than 10-fold lower. [5,17]

What Is MOTS-c?

MOTS-c (mitochondrial open-reading-frame of the 12S rRNA-c) is described as a 16–amino-acid, mitochondria-derived peptide (MDP) naturally produced in the human body. [1] The guide text discusses MOTS-c in relation to metabolism, weight loss, physical performance, and longevity research. [1]

The guide also summarizes literature describing mitochondria-derived peptides as having a cytoprotective role in maintaining mitochondrial function and cell viability under stress. [2]

Mechanistic discussion highlights

  • MOTS-c is discussed as being present in skeletal muscle and other organs (e.g., liver, brain). [1]
  • Guide text describes increased glucose uptake in muscle cells via activation of the AMPK pathway, without increasing insulin. [1,3,4]
  • The peptide is described as “exercise-mimetic” in the guide; exercise is reported to induce endogenous MOTS-c expression in skeletal muscle and circulation in humans. [5]

MOTS-c Benefits (Research Context)

The items below summarize findings and hypotheses described in the guide and cited literature. These are research findings, not clinical claims.

Body composition / metabolism

  • Guide text describes effects on skeletal muscle energy use and glucose metabolism, including AMPK activation via folate-cycle interactions. [3,4]
  • A mouse high-fat diet study is cited in the guide as showing MOTS-c prevented diet-induced obesity. [3,6]
  • AMPK-related gene expression links are discussed in the guide in relation to inflammation-associated weight gain. [3]

Longevity (genetics / population context)

  • The guide cites work discussing an mtDNA polymorphism (m.1382A>C) in the MOTS-c encoding region and a possible role in Japanese longevity. [7]
  • That study is summarized in the guide as proposing a biological link between MOTS-c and extended lifespan via putative endocrine action. [7]

Insulin sensitivity / insulin resistance

  • Guide text describes prevention of diet-induced and age-dependent muscle insulin resistance in mice, discussing metabolic homeostasis regulation. [4]
  • A human study cited in the guide reports plasma MOTS-c levels were positively associated with insulin sensitivity in lean (but not obese) individuals. [8]

Muscle atrophy signaling (myostatin)

  • The guide cites a 2021 study reporting an inverse correlation between plasma MOTS-c and myostatin in humans, and proposes inhibition of muscle-wasting gene activity via AKT phosphorylation. [9]

Bone health (animal models)

  • A rat osteoporosis context is described in the guide as showing stimulation of calcified nodule formation and upregulation of TGF-β/Smad pathway–related genes. [10]
  • An ovariectomy mouse model is summarized in the guide as reporting alleviation of bone loss, with dosing described as 5 mg/kg once daily for 12 weeks in that study. [11]

MOTS-c Side Effects / Safety Notes

The guide emphasizes that MOTS-c is a research peptide and has not undergone large-scale safety studies in humans. It notes that safety information exists for CB4211, described as an analog evaluated in a phase 1a/1b double-blind, placebo-controlled clinical trial in healthy adults, reported as safe and well-tolerated. [12,13,14]

Sex-based differences discussed

The guide describes reported sex-based differences in MOTS-c disruption in metabolic disease contexts and discusses hypotheses involving estrogen’s protective effects in premenopausal women. [15,16]

Drug pathway overlap (AMPK)

Because the guide describes MOTS-c as activating AMPK, it notes potential interaction/overlap with other AMPK-activating drugs (example given: metformin). [16]

Any protocol design should use appropriate oversight, endpoints, and inclusion/exclusion criteria aligned to institutional requirements.

Dosage Calculator and Guide (Research Context)

The guide describes MOTS-c as requiring reconstitution with bacteriostatic water prior to use in the described workflow and discusses subcutaneous administration as part of the example protocol narrative. [5]

Timing note (as described)

The guide suggests administering in the morning, noting it may interfere with sleep in research subjects. [5]

Sample protocol for weight loss (guide example)

Parameter Guide Example
Dose 5 mg in the morning (guide narrative; preferably before exercise) [5]
Frequency Every 5 days [5]
Study duration 20 days [5]
Repeat Second identical cycle within ~6 months after completing the first (guide recommendation) [5]

The guide also discusses that available animal data include dosing up to 15 mg/kg/day three days per week, while suggesting potential experimental human-trial dosing should be more than 10-fold lower. [5,17] It further states a recommendation to administer doses no greater than 5–10 mg/day and no more frequently than 1–3 times per week (as a research-summary statement). [5]

Reconstitution / Handling (Laboratory Context)

The steps below are presented as a high-level handling overview based on the guide text (not a clinical instruction).

High-level steps (guide text)

  1. Remove vial tops and wipe surfaces with an alcohol swab. [5]
  2. Use a sterile drawing syringe to draw bacteriostatic water (guide notes 1–2 mL is typical, dose-dependent). [5]
  3. Slowly transfer diluent into the MOTS-c vial, letting it trickle down the side while dissolving. [5]
  4. Do not shake or stir; solution should appear clear when fully mixed. [5]
  5. Store unused solution in refrigeration for future use. [5]

Handling note

The guide emphasizes that shaking may compromise the peptide and highlights clarity of solution when mixed. [5]

Bacteriostatic Water & Lab Supplies (Guide Summary)

The guide describes that peptide workflows may require supplies for reconstitution, administration, and storage, listing examples such as bacteriostatic water, sterile vials, and insulin syringes. [5]

Category Examples listed in guide
Diluent Bacteriostatic water [5]
Syringes / needles Insulin syringes; large needles + syringes [5]
Aseptic supplies Alcohol prep pads [5]
Containers Sterile empty glass vials [5]

Dosing Discussion (Verdict Summary)

The guide concludes there is limited human data on the mitochondria-derived peptide MOTS-c while summarizing reported outcomes discussed in the cited research, including body composition and metabolic effects, insulin sensitivity, myostatin-related signaling, and bone health findings in animal models. [3,4,8,9,10,11]

Overall, dosing concepts presented here are research-summary statements and should be confined to controlled laboratory or regulated clinical research contexts.

References

  1. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182-187. doi:10.1016/j.freeradbiomed.2016.05.015
  2. Yang Y, Gao H, Zhou H, Liu Q, Qi Z, Zhang Y, Zhang J. The role of mitochondria-derived peptides in cardiovascular disease: Recent updates. Biomed Pharmacother. 2019 Sep;117:109075. doi:10.1016/j.biopha.2019.109075. Epub 2019 Jun 8. PMID: 31185388.
  3. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54. doi:10.1016/j.cmet.2015.02.009. PMID: 25738459; PMCID: PMC4350682.
  4. 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 Sep 4;28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008. Epub 2018 Jul 5. PMID: 29983246; PMCID: PMC6185997.
  5. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021 Jan 20;12(1):470. doi:10.1038/s41467-020-20790-0. PMID: 33473109; PMCID: PMC7817689.
  6. Randrianarisoa E, Lehn-Stefan A, Krier J, Böhm A, Heni M, Hrabě De Angelis MH, Fritsche A, Häring H-U, Stefan N, Staiger H. AMPK Subunits Harbor Largely Nonoverlapping Genetic Determinants for Body Fat Mass, Glucose Metabolism, and Cholesterol Metabolism. J Clin Endocrinol Metab. 2020;105(1):14–25. https://doi.org/10.1210/clinem/dgz020
  7. Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A, Hirose N. The mitochondrial-derived peptide MOTS-c: A player in exceptional longevity? Aging Cell. 2015;14. doi:10.1111/acel.12389
  8. Cataldo LR, Fernández-Verdejo R, Santos JL, et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med. 2018;66:1019-1022.
  9. Kumagai H, Coelho AR, Wan J, Mehta HH, Yen K, Huang A, et al. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab. 2021;320(4):E680-E690. doi:10.1152/ajpendo.00275.2020. PubMed PMID: 33554779
  10. Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018 Nov;22(21):7156-7163. doi:10.26355/eurrev_201811_16247. PMID: 30468456.
  11. Ming W, Lu G, Xin S, Huanyu L, Yinghao J, Xiaoying L, Chengming X, Banjun R, Li W, Zifan L. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochem Biophys Res Commun. 2016 Aug 5;476(4):412-419. doi:10.1016/j.bbrc.2016.05.135. Epub 2016 May 26. PMID: 27237975.
  12. A phase 1A/1B study of CB4211 in healthy non-obese subjects and subjects with nonalcoholic fatty liver disease – full text view. ClinicalTrials.gov. Retrieved September 18, 2022, from https://clinicaltrials.gov/ct2/show/NCT03998514
  13. BioSpace. (2019, November 5). CohBar completes phase 1a and initiates phase 1b stage of clinical trial of CB4211 under development for NASH and Obesity. Retrieved September 18, 2022, from https://www.biospace.com/article/releases/cohbar-completes-phase-1a-and-initiates-phase-1b-stage-of-clinical-trial-of-cb4211-under-development-for-nash-and-obesitymilestone-for-first-mitochondrial-based-therapeutic-in-humans/
  14. Cundy KC, Grindstaff K, Magnan R, et al. (2017). CB4209 and CB4211 Reduce the NAFLD Activity Score in the STAM Model of NASH, Reduce Triglyceride Levels, and Induce Selective Fat Mass Loss in DIO Mice. Poster. AASLD Meeting 2017.
  15. Du C, Zhang C, Wu W, et al. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatr Diabetes. 2018;19:1058–1064. https://doi.org/10.1111/pedi.12685
  16. MOTS-c – alzdiscovery.org. Retrieved September 18, 2022, from https://www.alzdiscovery.org/uploads/cognitive_vitality_media/MOTS-c.pdf

Educational content for research discussion only. Not medical advice.