Dosage research on MOTS-c

Preclinical research dose ranges

In published preclinical research on MOTS-c, administered dose ranges in rodent metabolic models have most commonly fallen in the 0.1 to 5 milligram per kilogram range delivered intraperitoneally. The seminal high-fat-diet murine studies from Lee and colleagues used doses in this range across multi-week protocols, with the 5 milligram per kilogram dose level appearing as the upper-end study dose in the published insulin-sensitivity and adiposity work.

The skeletal-muscle and exercise-mimetic literature has used a comparable dose range. Investigators publishing on AMPK pathway activation in skeletal muscle have used 0.5 to 5 milligrams per kilogram intraperitoneal administration in mice and rats. Acute pharmacokinetic work has used single-bolus intravenous dosing at the low end of the range for half-life characterisation.

In-vitro studies on cultured myotubes, hepatocytes, and adipocytes have most commonly used MOTS-c at micromolar concentrations in the culture medium, with effects on glucose uptake and mitochondrial respiration reported across the 0.1 to 10 micromolar range. The in-vitro and in-vivo dose conventions are not directly translatable to one another because of the pharmacokinetic considerations involved in systemic delivery, and investigators choose between the two based on the endpoint being measured.

Dose-response considerations from the published literature

The published MOTS-c literature has reported dose-response characteristics in the insulin-sensitivity and metabolic-flexibility endpoints across the 0.1 to 5 milligram per kilogram range in murine high-fat-diet models. Effects on glucose tolerance and on adiposity scaled with dose across that span. The skeletal-muscle AMPK activation work has reported a comparable dose-response curve in vivo, with the in-vitro mechanistic work providing the pathway-level corroboration.

No Phase 1 or Phase 2 dose-ranging trial of MOTS-c has appeared in the indexed clinical-trial literature at the time of writing. The compound remains in preclinical and translational research, and the research community continues to rely on the rodent in-vivo and cell-culture literature for dose-design inference.

Reconstitution math and per-vial dose calculation

A 10 mg lyophilised MOTS-c vial reconstituted with 1 mL of bacteriostatic water yields a stock concentration of 10 mg per mL, which is the most common stock concentration in published rodent protocols using MOTS-c from research-grade lyophilised vials. From this stock, a research aliquot of 0.1 mL contains 1 milligram; an aliquot of 0.05 mL contains 500 micrograms. Researchers working in the milligram-per-kilogram dose ranges reported in published rodent in-vivo experiments further dilute the stock to a working concentration appropriate to the model and the body weight of the animal subject. Refrigerated storage at 2 to 8 degrees Celsius, protected from light, is the standard handling practice reported across the rodent in-vivo work.

Research-protocol design considerations

Protocol-design choices in the published MOTS-c literature reflect recurring considerations. Dose selection in murine metabolic models anchors at the 0.5 to 5 milligram per kilogram range and varies with the endpoint. Acute pharmacokinetic studies use single-bolus dosing at the low end of that range. Chronic metabolic studies use multi-week dosing protocols with intraperitoneal administration two to three times per week being a common cadence.

Route of administration in the published rodent work is most often intraperitoneal. Subcutaneous administration appears in a smaller subset of studies. Intravenous administration appears in pharmacokinetic and acute-effect studies. In-vitro studies on cultured cells deliver MOTS-c directly into the culture medium at micromolar concentrations.

The mitochondrial-DNA origin of MOTS-c is a protocol-design consideration unique among peptides commonly handled as lyophilised research vials. The peptide sequence corresponds to an open reading frame within the 12S rRNA region of mitochondrial DNA, and investigators sometimes contrast MOTS-c effects with effects of other mitochondrial-derived peptides in the same protocol to characterise pathway specificity.

References

1. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 2015. [PMID 25738459]
2. Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 2021. [PMID 33293544]
3. Kim SJ et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological Reports, 2019. [PMID 31496140]
4. Mendelsohn AR, Larrick JW. Mitochondrial-derived peptides exacerbate senescence. Rejuvenation Research, 2018. [PMID 30269657]
5. Lu H et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. Journal of Molecular Medicine, 2019. [PMID 31055609]
6. Yin Y et al. The peptide MOTS-c regulates mitochondrial function and metabolism. Aging Cell, 2018. [PMID 30269632]