# MOTS-c Dosage in the Research Literature — Studied Ranges and PK Data

> MOTS-c dosage ranges from the published literature: 0.5–15 mg/kg in rodent models, early self-experiment protocols, reconstitution, half-life, and route considerations. No therapeutic dose is established.

## Studied MOTS-c Dosage Ranges

MOTS-c dosage in the peer-reviewed literature spans a wide range depending on model and endpoint:

| Model | Dose | Route | Duration | Study |
|---|---|---|---|---|
| Diet-induced obese mice (metabolic) | 15 mg/kg/day | Intraperitoneal | Chronic | Lee 2015 [1] |
| Diet-induced obese mice (low-dose arm) | 2.5 mg/kg/day | Intraperitoneal | Chronic | Lee 2015 [1] |
| Obese mice (metabolomics) | 2.5 mg/kg BID | Intraperitoneal | 3 days | Kim 2019 [5] |
| Aged mice (healthspan/endurance) | 5 mg/kg 3×/week | Subcutaneous | Chronic late-life | Reynolds 2021 [2] |
| Cardiac pressure-overload mice | 5 mg/kg/day | SC (osmotic pump) | 4 weeks | Zhong 2022 [10] |
| Type-2-diabetic rats (cardiac) | 15 mg/kg/day | Intraperitoneal | 3 weeks | Pham 2025 [11] |
| Human myotubes (in vitro) | 10 µM | Culture media | — | Elhusseiny 2026 [13] |

No therapeutic dose has been established in a controlled clinical trial. Human self-experiment protocols typically cite 5–10 mg/week subcutaneous, but these are not from peer-reviewed trials.

## MOTS-c Half-Life and Pharmacokinetics

Formal pharmacokinetic half-life data for exogenous subcutaneous MOTS-c administration have not been published as of 2025.

Human exercise induces an 11.9-fold increase in skeletal muscle MOTS-c expression and a 1.5–1.6-fold rise in circulating plasma MOTS-c, with levels returning toward baseline within approximately four hours post-exercise [3]. This documents the endogenous elimination timecourse.

For exogenous administration: published efficacy studies used osmotic pumps or multi-weekly injection protocols designed to maintain sustained exposure rather than characterize plasma half-life [2][10]. No plasma concentration-time curve data are available.

## Oral vs Subcutaneous Delivery

Subcutaneous injection is the route used in virtually all published efficacy studies. MOTS-c as a 16-amino-acid peptide is subject to rapid proteolytic degradation in the gastrointestinal tract. Oral bioavailability has not been validated in comparative PK studies [2][10].

## Reconstitution and Storage

Lyophilized (freeze-dried) MOTS-c is stable for extended periods at -20°C. Typical reconstitution in research protocols uses bacteriostatic water at 1–2 mL per 10 mg vial. Reconstituted solutions are stored at 4°C and used within a short window. Repeated freeze-thaw cycles reduce peptide integrity. Research-grade MOTS-c is a chemical reagent, not a pharmaceutical product.

## Administration Timing

Mouse studies administered MOTS-c subcutaneously before treadmill exercise sessions in the Reynolds et al. 2021 endurance arm [2]. No circadian or meal-timing optimization data from human trials exist.

## MOTS-c and Metformin: Overlapping Mechanisms

Both MOTS-c and metformin activate AMPK via different upstream mechanisms. Metformin inhibits mitochondrial Complex I (raising AMP/ATP ratio); MOTS-c inhibits the folate cycle (accumulating AICAR) [1][17]. No controlled human study has examined the combination.

## References

[1] Lee C, et al. Cell Metabolism. 2015;21(3):443-454. DOI: 10.1016/j.cmet.2015.02.009 PMID: 25738459

[2] Reynolds JC, et al. Nature Communications. 2021;12(1):773. DOI: 10.1038/s41467-020-20790-0 PMID: 33473109

[3] Reynolds JC, et al. [Human exercise data.] Nature Communications. 2021;12(1):773. PMID: 33473109

[5] Kim SJ, et al. Physiological Reports. 2019;7(13):e14171. DOI: 10.14814/phy2.14171 PMID: 31293078

[10] Zhong P, et al. JCMM. 2022;26(21):5672-5683. DOI: 10.1111/jcmm.17551 PMID: 36156853

[11] Pham T, et al. Frontiers in Physiology. 2025;16:1602271. DOI: 10.3389/fphys.2025.1602271 PMID: 40661667

[13] Elhusseiny R, et al. Physiological Reports. 2026;14(4):e70791. DOI: 10.14814/phy2.70791 PMID: 41732124

[17] Wan W, et al. J Transl Med. 2023;21(1):36. DOI: 10.1186/s12967-023-03885-2 PMID: 36670507

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Calibrated from the peer-reviewed record — a machined-instrument digest of the MOTS-c literature, not a clinic, not a vendor, not a prescription.