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MOTS-c Sleep Architecture Impact: What the Evidence Actually Shows

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At a glance

  • What it is / A 16-amino-acid peptide encoded in mitochondrial DNA [1][2]
  • Sleep stages recorded after a dose in people / No study found [1]
  • Human dosing studies / None; nominated products were 5 mg and 10 mg injections [1]
  • Administered-MOTS-c effect data / Cells and mice only; human studies measured the body's own MOTS-c after exercise [1][2][3][7]
  • Regulatory status / Not FDA-approved; in none of the three categories on FDA's compounding list for pharmacies and physicians [1][4]
  • Sport status / Prohibited at all times by WADA, S4.4.1 [5]
  • Injectable concern / Immunogenicity from aggregation and peptide-related impurities [1][6]

Does MOTS-c change sleep architecture?

Unknown. Sleep architecture is the pattern of non-REM and REM sleep stages across a night, assessed with polysomnography. No study has measured sleep stages, delta power or circadian timing after MOTS-c in people [1].

What the mouse studies measured

In mice, MOTS-c prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity, with skeletal muscle as the main target and AMPK activated downstream of inhibited folate-cycle metabolism [2]. Injected at 0.5 mg/kg/day intraperitoneally, it gave roughly 20% lower body weight than controls after 8 weeks on a high-fat diet [1]. Late-life intermittent treatment (15 mg/kg three times weekly from 23.5 months) raised median lifespan from 912 to 970 days [1][3]. The endpoints were body weight, insulin sensitivity, exercise capacity and lifespan, not sleep stages.

The human studies measured the body's own peptide

Exercise raises endogenous MOTS-c expression in human skeletal muscle and circulation; those participants were not given the peptide [3]. In a randomized trial of 30 healthy adults, 10 cycled for 45 minutes at 70% of estimated VO2max, 10 did resistance exercise and 10 were controls. Circulating humanin rose significantly after endurance exercise, MOTS-c showed only a trend to increase, and plasma levels were not related to fitness [7]. None of this tested an injected dose or sleep measures.

Dose and safety

There is no approved dose and no human dosing study [1]. The nominated products were 5 mg and 10 mg subcutaneous injections, and sleep was not among the uses FDA reviewed [1][8]. Rodent doses of 0.5 to 15 mg/kg cannot be converted into a human dose [1]. FDA's adverse-event database searches through March 9, 2025 retrieved no MOTS-c reports, but the agency found no human exposure data and no animal toxicity studies [1]. Its stated concern for injections is immunogenicity from aggregation and peptide-related impurities [1][6].

Frequently asked questions

Does MOTS-c improve slow-wave sleep?
No published study has measured sleep stages or delta power after MOTS-c in people [1]. The human work tracks the body's own peptide after exercise, not an injected dose [3][7].
Is MOTS-c approved, and can it be compounded?
It is not FDA-approved and appears in none of the three categories on FDA's compounding list for state-licensed pharmacies and physicians [1][4][9][10]. FDA staff recommended against adding it to the bulks list. A July 23, 2026 advisory committee vote in its favor was non-binding, and HHS's October 2026 enforcement-discretion policy is a draft, non-binding statement and not an approval [1][8][11].
What dose was studied in humans?
None. No human dosing study exists; the nominated products were 5 mg and 10 mg injections, and rodent doses do not translate into a human dose [1].
Is MOTS-c banned in sport?
Yes. WADA names it in S4.4.1 as an AMPK activator and prohibits it at all times, in and out of competition [5][12].
Is injected MOTS-c safe?
Safety in people is unknown: FDA found no human exposure data and no animal toxicity studies, and cites immunogenicity risk from aggregation and impurities in injectable peptides [1][6].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-54. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
  3. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, 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. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
  4. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  5. World Anti-Doping Agency. World Anti-Doping Agency
  6. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA
  7. von Walden F, Fernandez-Gonzalo R, Norrbom J, Emanuelsson EB, Figueiredo VC, Gidlund EK, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021;131(3):1035-1042. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
  8. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  9. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  10. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA
  11. Official web page. Official web page
  12. World Anti-Doping Agency. World Anti-Doping Agency
Evidence overview for MOTS-c Sleep Architecture Impact: What the Evidence Actually Shows