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MOTS-c Side Effects: Severity Distribution by Patient Phenotype

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At a glance

  • Stated injection concern / Immunogenicity from aggregation and peptide impurities [2]
  • Regulatory status / Not FDA-approved; not in any category on FDA's compounding lists [1][3][4][5]
  • Forms nominated / 5 mg and 10 mg subcutaneous injections [1]
  • Animal findings / Weight, insulin sensitivity and performance effects in mice only [1]
  • Human exposure data / None found by FDA by any route [1]

Is there a severity distribution for MOTS-c side effects?

No. The FDA's July 2026 evaluation searched PubMed, Embase, the Cochrane library and other sources and found no published study in which MOTS-c was given to a person, and its adverse-event database searches retrieved no MOTS-c reports through March 9, 2025 [1]. There are no reliable data from which to calculate severity by patient group.

What has the FDA said about the injection?

FDA's stated concern for injected peptides is immunogenicity, an immune reaction to aggregates and peptide-related impurities [2]. MOTS-c is 16 amino acids long and no immunogenicity data exist for it [1]. The nominated products were 5 mg and 10 mg subcutaneous injections [1]. FDA also noted an in-vitro study in which MOTS-c is quickly broken down in human blood, which raises the question whether injecting it can produce active levels in people [1].

What do the animal studies show?

In mice, injected MOTS-c reduced weight gain on a high-fat diet (about 20% lower body weight after 8 weeks at 0.5 mg/kg/day intraperitoneally) and improved insulin sensitivity and exercise performance [1]. In one study, a late-life schedule of 15 mg/kg three times weekly from 23.5 months of age lengthened median lifespan from 912 to 970 days [1][6]. FDA noted that the molecular targets are unknown and no dose-response relationships were assessed, and the rodent mg/kg doses cannot be converted into human doses [1]. FDA found no animal toxicity studies [1].

What do the human studies measure?

A 2021 study found that exercise raises the body's own MOTS-c in human skeletal muscle and in circulation; the injections in that study were given to mice [6]. A randomised trial of 30 healthy adults, split into endurance exercise (n=10), resistance exercise (n=10) and control (n=10), found circulating humanin rose after endurance exercise while MOTS-c showed only a trend to increase; plasma MOTS-c was not related to fitness [7]. In the human parts of these studies nobody was given MOTS-c, so they say nothing about side effects after an injection [6][7].

Do age, weight, diabetes or mitochondrial disease change the risk?

Because FDA found no study in which people were given MOTS-c, injection reactions cannot be compared by age, weight, diabetes status or mitochondrial disease [1]. The nearest human evidence concerns metabolic biology rather than reactions. A meta-analysis of three cohorts (n=27,527) found that men, but not women, carrying the m.1382A>C variant had a higher prevalence of type 2 diabetes [8]. In the same paper, injected MOTS-c reduced weight and improved glucose tolerance in high-fat-fed male mice, while female mice were unaffected [8]. Neither finding reports the frequency or grade of a reaction after an injection.

Frequently asked questions

Is MOTS-c FDA approved?
No. MOTS-c is not an FDA-approved drug and is not a component of one, and it is in none of the categories on FDA's compounding lists [1][3][4][5].
What is the FDA's stated concern about injected MOTS-c?
Immunogenicity, an immune reaction to aggregates and peptide-related impurities. MOTS-c is 16 amino acids long and no immunogenicity data exist for it [2][1].
What did the animal studies show?
In mice, injected MOTS-c reduced weight gain on a high-fat diet and improved insulin sensitivity and exercise performance; one late-life schedule lengthened median lifespan from 912 to 970 days. The rodent doses cannot be converted into human doses [1].
Do the human studies test injected MOTS-c?
No. They measured the body's own MOTS-c; exercise raises it in muscle and blood, but no person received the peptide [6][7].
How are reactions to unapproved peptides reported?
The FDA's MedWatch program accepts reports from health professionals and the public [9].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. 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
  3. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  4. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  5. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA
  6. 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
  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. Zempo H, Kim SJ, Fuku N, Nishida Y, Higaki Y, Wan J, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
  9. MedWatch: The FDA Safety Information and Adverse Event Reporting Program | FDA. MedWatch: The FDA Safety Information and Adverse Event Reporting Program | FDA
Evidence overview for MOTS-c Side Effects: Severity Distribution by Patient Phenotype