What Does the Research Say?

Studies of MOTS-c fall into three groups: experiments in animals, observations in people and questions about how to measure it.

Studies in Mice

• Metabolism (Cell Metab, 2015): injections prevented insulin resistance linked to age and to a high-fat diet, and prevented diet-induced obesity.
• Gene control (Cell Metab, 2018): under glucose restriction, MOTS-c entered the nucleus and interacted with NRF2, a key regulator of antioxidant genes.
• Physical capacity (Nat Commun, 2021): treated mice of all ages performed better, and three weekly doses started in old age improved physical capacity and healthspan.

Studies in People

• Exercise (2021): exercise raised MOTS-c in human skeletal muscle and in the blood.
• Diabetes genetics (Aging, 2021): an analysis of three cohorts with 27,527 people found that men carrying the K14Q variant had a higher prevalence of type 2 diabetes, especially the least active. Women showed no such link. In mice, the variant peptide did not improve glucose tolerance as normal MOTS-c did.
• Muscle fibres (2022): in Japanese participants, carriers of the same variant had more fast-twitch fibres. It was more common in sprint and power athletes (6.5%) than in controls (5.1%) or endurance athletes (2.9%).
• Strength (Int J Mol Sci, 2023): in 20 active volunteers, higher resting serum MOTS-c went with more muscle mass and jumping power, but not with aerobic capacity.

A Measurement Problem

The Cologne anti-doping laboratory developed a mass spectrometry test sensitive to 100 picograms per millilitre. When it compared results with a commercial antibody test, it could not confirm the natural blood levels the antibody kit reported, around 46 to 219 nanograms per millilitre. This casts doubt on some published values of MOTS-c in human blood.

What Is Missing

• No published controlled trial has tested MOTS-c itself in humans.
• The only registered trial of a related compound, CB4211, has no posted results.
• Much of the key research comes from the discovering group, whose members disclosed commercial ties.
• Long-term effects of raising MOTS-c above natural levels are unknown.

Summary

MOTS-c is a real, measurable signal from mitochondria with striking effects in mice. Whether giving it to people would help, and at what risk, has not been studied in published trials.

References

1. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21:443-454. PMID 25738459
2. 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;28:516-524. PMID 29983246
3. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Commun Mass Spectrom. 2019;33:371-380. PMID 30394592
4. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. PMID 33473109
5. Zempo H, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13:1692-1717. PMID 33468709
6. Kumagai H, et al. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochim Biophys Acta Gen Subj. 2022;1866:130048. PMID 34728329
7. Domin R, et al. MOTS-c serum concentration positively correlates with lower-body muscle strength and is not related to maximal oxygen uptake. Int J Mol Sci. 2023;24:14951. PMID 37834399