# MOTS-c - Canonical: https://residue.info/c/mots-c/ - Also called: Mitochondrial open reading frame of the 12S rRNA-c, MOTSc - Evidence grade: D (Preclinical only). Effects of giving MOTS-c are shown only in cells and mice. Human studies measure naturally occurring levels; a phase 2 trial is recruiting. - Status: Not FDA-approved · FDA compounding nomination withdrawn - PubChem CID: 146675088 - Updated: 2026-10-19 · Reviewed by: Residue Editorial Team MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. In mice, it prevented diet-induced obesity and age- and diet-related insulin resistance [1] and improved physical performance at all ages [2]. Human studies so far measure natural blood levels [3]; FDA has identified no human exposure data for MOTS-c products [4]. ## Key findings - MOTS-c is encoded by a short open reading frame within the mitochondrial 12S rRNA gene; its primary target appears to be skeletal muscle, where it inhibits the folate cycle and activates AMPK [1]. (anchor: https://residue.info/c/mots-c/#kf-pmid-25738459) - MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity in mice [1]. (anchor: https://residue.info/c/mots-c/#kf-pmid-25738459-2) - It enhanced physical performance in young, middle-aged and old mice; treatment started at 23.5 months increased physical capacity and healthspan [2]. (anchor: https://residue.info/c/mots-c/#kf-pmid-33473109) - In humans, exercise induced MOTS-c expression in muscle and blood [2]; plasma levels were similar in 10 lean and 10 obese people [3]. (anchor: https://residue.info/c/mots-c/#kf-pmid-33473109-2) - FDA lists MOTs-C among withdrawn compounding nominations, with no identified human exposure data and possible significant immunogenicity risk [4]. (anchor: https://residue.info/c/mots-c/#kf-fda-cat2) ## Effects by system - Insulin sensitivity (mice) (grade D): Prevented diet- and age-induced insulin resistance [1]. (anchor: https://residue.info/c/mots-c/#effect-insulin-sensitivity-mice) - Physical capacity (mice) (grade D): Improved performance and healthspan, including late-life treatment [2]. (anchor: https://residue.info/c/mots-c/#effect-physical-capacity-mice) - Muscle atrophy (grade D): Lowered plasma myostatin in obese mice and prevented myotube atrophy in vitro [5]. (anchor: https://residue.info/c/mots-c/#effect-muscle-atrophy) - Human physiology (grade D): Endogenous levels rise with exercise [2] and correlate with insulin-sensitivity indices in lean people [3] — observational only. (anchor: https://residue.info/c/mots-c/#effect-human-physiology) ## What is MOTS-c? Most proteins are encoded in the cell nucleus, but mitochondria carry their own small genome. In 2015, researchers reported a short open reading frame within the mitochondrial 12S rRNA gene encoding a 16-amino-acid peptide they named MOTS-c [1]. PubChem's record gives its sequence as Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (Figure 1) [6]. A review describes MOTS-c moving into the nucleus during metabolic stress to direct nuclear gene expression [7]. ## How is MOTS-c thought to work? The discovery paper identified skeletal muscle as the primary target. In cells, MOTS-c inhibits the folate cycle and the de novo purine biosynthesis linked to it, which activates AMPK, a central energy sensor [1]. Later work found it reduces myostatin and muscle-atrophy signaling through AKT, FOXO1, mTORC2, PTEN and CK2 [5]. ## What have studies found? **Metabolism in mice.** MOTS-c treatment prevented both age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity [1]. **Aging and exercise in mice.** A 2021 Nature Communications study found MOTS-c significantly enhanced physical performance in young (2 months), middle-aged (12 months) and old (22 months) mice, and that intermittent treatment three times a week started in late life (23.5 months) increased physical capacity and healthspan [2]. **Muscle.** Plasma MOTS-c correlated inversely with myostatin in human subjects; MOTS-c prevented palmitic-acid-induced atrophy in muscle cells and lowered plasma myostatin in diet-induced obese mice [5]. **Humans.** Exercise induced endogenous MOTS-c in human skeletal muscle and circulation [2]. In 10 lean and 10 obese adults, plasma MOTS-c was similar (0.48 versus 0.52 ng/mL) but correlated with insulin-resistance indices, mainly in lean individuals [3]. A 2023 review concluded that no effective method of applying MOTS-c in the clinic had yet been developed [7]. At our fetch, ClinicalTrials.gov listed a recruiting phase 2 study in prediabetes with overweight or obesity [8]. FDA's entry for "MOTs-C" warns of possibly significant immunogenicity risk and complexities in impurity and API characterization. It states FDA has not identified any human exposure data on products containing MOTS-c by any route and lacks important information about whether it would cause harm in humans [4]. ## What is still unknown? - **Human pharmacology and safety** of administered MOTS-c are unknown; the registered phase 2 trial may provide the first data [8]. - **Translation** of mouse aging and metabolism effects to people. ## Frequently asked questions **What is MOTS-c?** A 16-amino-acid peptide encoded by a short open reading frame in the mitochondrial 12S rRNA gene, described in 2015 as a regulator of insulin sensitivity and metabolic homeostasis [1]. **Has MOTS-c been tested in humans?** Not as a treatment in any published study we found. Human research has measured natural levels — rising with exercise [2] and relating to insulin sensitivity in lean people [3]. A phase 2 trial in prediabetes is registered as recruiting [8]. **Is MOTS-c FDA-approved?** No. FDA lists MOTs-C among withdrawn compounding nominations and says it has not identified any human exposure data and lacks information on whether it would cause harm [4]. **How is MOTS-c different from SS-31 (elamipretide)?** MOTS-c is a naturally encoded mitochondrial peptide with mouse data only [1]; elamipretide is a synthetic cardiolipin-binding peptide with randomized trials and an FDA accelerated approval for Barth syndrome [9]. **Does MOTS-c decline with age?** A 2023 review states that plasma MOTS-c levels decrease with age [7]. ## Sources [1] The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Lee C et al. Cell Metab. 2015. https://pubmed.ncbi.nlm.nih.gov/25738459/ [2] MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Reynolds JC et al. Nat Commun. 2021. https://pubmed.ncbi.nlm.nih.gov/33473109/ [3] Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Cataldo LR et al. J Investig Med. 2018. https://pubmed.ncbi.nlm.nih.gov/29593067/ [4] Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026. https://www.fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks [5] MOTS-c reduces myostatin and muscle atrophy signaling. Kumagai H et al. Am J Physiol Endocrinol Metab. 2021. https://pubmed.ncbi.nlm.nih.gov/33554779/ [6] PubChem compound record: Mots-c. C101H152N28O22S2 · MW 2174.6 g/mol. https://pubchem.ncbi.nlm.nih.gov/compound/146675088 [7] MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Zheng Y et al. Front Endocrinol (Lausanne). 2023. https://pubmed.ncbi.nlm.nih.gov/36761202/ [8] MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Hudson Biotech · PHASE2 · recruiting. https://clinicaltrials.gov/study/NCT07505745 [9] FORZINITY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2025-12-10. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=146bf34c-76f2-48db-ac07-fb29cce2cd75 --- From Residue. Research and education only; not medical advice. Quote with attribution and a link to the canonical page.