MOTS-c Super-Responder Profile: Who Gets the Best Results and Why

Where the responder idea comes from: mice

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA. Its main target appears to be skeletal muscle, where its cellular actions inhibit the folate cycle and its tethered purine biosynthesis, leading to AMPK activation [2]. In mice, treatment prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity [2]. A second mouse study found that MOTS-c improved physical performance at 2, 12 and 22 months of age, and that intermittent treatment started at 23.5 months increased physical capacity and healthspan [3]. FDA noted that the molecular targets are unknown, that no dose-response relationships were assessed, and that rodent doses (0.5 to 15 mg/kg) cannot be converted into human doses [1].

The human studies measured natural MOTS-c, not injections

Reynolds et al. 2021 reported that exercise induces endogenous MOTS-c expression in human skeletal muscle and in circulation [3]. In von Walden et al. 2021, 30 healthy adults were randomized to endurance exercise (n=10), resistance exercise (n=10) or control (n=10). Circulating humanin rose after endurance exercise, while MOTS-c showed only a trend to increase. Plasma MOTS-c was not related to VO2max, leg strength or muscle mitochondrial DNA copy number [4]. In both studies nobody was given MOTS-c, so neither can say who would respond to an injection.

One genetic variant

The m.1382A>C variant (rs111033358) replaces lysine with glutamine at position 14 of the peptide [6]. In a meta-analysis of three cohorts totalling 27,527 people, men but not women carrying the C allele had a higher prevalence of type 2 diabetes [6]. In high-fat-fed male mice injected with MOTS-c, weight fell and glucose tolerance improved, but mice injected with the K14Q peptide did not improve, and female mice were unaffected [6]. The human finding concerns the variant, and the injections were tested only in mice.

Regulatory status and known risks

FDA's adverse-event database searches through March 9, 2025 retrieved no MOTS-c reports. FDA found no human exposure data and no animal toxicity studies, and its stated concern for injectable peptides is immunogenicity from aggregation and peptide-related impurities [1][7]. MOTS-c is not FDA-approved. It sits in FDA's "nominated but withdrawn" table, which is not a finding that it is safe, and it is in none of the three categories on FDA's compounding lists for pharmacies and physicians or on its list for outsourcing facilities [1][7][8][9][10]. FDA staff recommended against adding it to the bulks list; the July 2026 advisory committee voted in favor, but that vote is non-binding [1][11]. HHS's October 2026 enforcement-discretion policy for MOTS-c acetate injection is a draft that is not binding and not an approval [12][13]. WADA names MOTS-c in S4.4.1, prohibited at all times in and out of competition [5].