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Growth Hormone Axis ResearchRegeneration ResearchPeptide BioregulatorsCognitive & Neuropeptide ResearchMetabolic & Cellular ResearchMelanocortin & Endocrine ResearchDermal Peptide ResearchImmune & Thymic ResearchMOTS-c is a peptide first described in 2015 [1]. No completed controlled human administration study of MOTS-c has published results, by any route and for any endpoint. There are no human efficacy data and no human safety data for it.
MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame within the mitochondrial 12S rRNA gene [1]. Its sequence MRWQEMGYIFYPRKLR sits in PubChem under CAS 1627580-64-6 at a free-peptide molecular weight of 2174.6, with no cysteine and so no disulfide bridge [2]. That CAS returns duplicate records, one named as a trifluoroacetate salt while carrying the free-peptide formula [2]. A database entry confirms a sequence, not that the peptide is translated inside a living cell. A 2026 eLife paper reframes MOTS-c as a mitochondrial-encoded, interferon-linked host defense peptide, a materially different identity from the metabolic regulator of consumer material [3].
The first registered trial to administer MOTS-c to people began recruiting on 2 February 2026 and has reported no results [4]. It is an industry-sponsored phase 2a randomized, double-blind, placebo-controlled study in adults with prediabetes and overweight or obesity, estimated enrollment 120 [4]. Its primary outcomes are an insulin sensitivity index from an oral glucose tolerance test, and treatment-emergent adverse events [4].
An analogue called CB4211 completed a phase 1a/1b trial in April 2021, and no results were ever posted or published [5]. CB4211 is a modified molecule and not MOTS-c, so its data would not be evidence about MOTS-c [5].
The discovery paper described inhibition of the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation, with skeletal muscle the apparent primary target [1]. In mice, MOTS-c prevented age-dependent and high-fat-diet-induced insulin resistance, and prevented diet-induced obesity [1]. These are animal and cell findings, and none of them has been shown in humans [1].
A later paper reported enhanced physical performance in young, middle-aged and old mice, with intermittent late-life treatment raising physical capacity and healthspan [6]. No human was administered MOTS-c in it, and two authors declared they were consultants and shareholders of CohBar, Inc., the company then developing a MOTS-c analogue [6].
Mouse work reported MOTS-c expression regulated by the AMPK and PGC-1alpha axis, with a high-fat diet markedly reducing skeletal muscle and plasma MOTS-c [7]. Treadmill training raised MOTS-c, PGC-1alpha and GLUT4 protein in those mice [7]. That is mechanism in animals rather than an outcome, and it establishes nothing about giving MOTS-c to a person [7]. The same work describes downstream AICAR accumulation in mice, which does not make the two compounds interchangeable [7].
Exercise raises MOTS-c in people; MOTS-c has never been given to a person in a completed published trial. The human component of the mouse performance paper is observational, reporting that exercise induces endogenous MOTS-c in human skeletal muscle and circulation [6]. A randomized human exercise study tempers that: acute endurance exercise significantly raised circulating humanin, while MOTS-c showed only a non-significant trend [8]. Acute resistance exercise raised neither peptide, and group sizes were 10 per arm [8]. Resting mitochondrial-derived peptide levels were not correlated with VO2max, leg strength or muscle mitochondrial DNA copy number [8].
A meta-analysis of 7 studies and 602 participants found circulating MOTS-c significantly reduced in diabetes, at a standardized mean difference of -0.89 (95% CI -1.12 to -0.65) [9]. The same analysis found it significantly increased in obesity, at +0.51 (95% CI 0.21 to 0.81), the opposite direction in an overlapping metabolic population [9]. A 2026 study found MOTS-c higher in adults with obesity than in lean adults, and unchanged six months after bariatric surgery despite significant BMI improvement (p=0.913) [10]. Its authors propose MOTS-c may be a compensatory response rather than a driver [10]. They describe the work as preliminary and exploratory, with 10 patients in the longitudinal surgical arm [10]. Any statement that MOTS-c simply declines in metabolic disease is unsupportable as written.
One prognostic study reported that low circulating MOTS-c, below a stated threshold, independently predicted major adverse cardiac events over two years in revascularized type 2 diabetics [11]. The result held in an external validation cohort, but the design is observational and prognostic only [11]. That makes MOTS-c a correlate of cardiovascular risk, not a lever on outcomes, with reverse causation and confounding unaddressed and nothing administered [11].
A short commentary proposed, as a hypothesis, that the m.1382A>C polymorphism in the MOTS-c-encoding region of mitochondrial DNA may contribute to Japanese longevity [12]. That variant is specific to Northeast Asian populations, the commentary's own language is that more research is needed, and it says nothing about administering MOTS-c [12].
A 2026 study in human mesenchymal stromal cells found basal MOTS-c expression lower in cells from people with obesity [13]. Exogenous MOTS-c restored intracellular levels and activated AMPK signaling, yet outcomes worsened: it reduced proliferation, increased senescence-associated expression of p16 and p21, and upregulated TNF-alpha [13]. In a mouse renal artery stenosis model, MOTS-c-pretreated obese cells failed to improve renal perfusion, fibrosis or tubular injury, and pretreatment blunted the reparative efficacy of lean cells [13]. The authors conclude that restoring mitochondrial metabolic signaling may paradoxically exacerbate senescence and inflammation [13]. This work is in vitro with a supporting mouse arm and uses 6 donors per group, so it does not establish that MOTS-c causes senescence in humans [13]. It does show that AMPK engagement, the mechanism usually cited as the benefit, is not by itself a benefit.
A narrative review characterizes MOTS-c as a candidate anti-pulmonary-fibrosis factor and describes it as being investigated as a potential exercise mimetic [14]. It is forward-looking and rests on preclinical material, so it documents where the exercise mimetic framing originates rather than showing efficacy [14].
MOTS-c is not approved for human therapeutic use, and Drugs@FDA holds no approved application for it [15]. Absence of approval is not itself a safety finding, and means only that efficacy and safety are unestablished to a regulator's standard [15].
MOTS-c is named on the 2026 WADA Prohibited List in section S4, hormone and metabolic modulators, as an activator of AMP-activated protein kinase [16]. Section S4 substances are prohibited at all times, in and out of competition [16]. It shares that entry with AICAR, but that is a regulatory grouping by proposed mechanism and transfers no findings between them [16]. Athletes should seek a binding determination from their own anti-doping organization.
A 2026 sports medicine review covers MOTS-c among unapproved peptides sold outside regulatory oversight [17]. Across the peptides it covers, it reports favorable tissue repair and metabolic outcomes in animal models, scarce rigorous human safety data, and potential for serious harm [17].
No completed controlled human administration study of MOTS-c has published results, by any route and for any endpoint. The first registered trial to administer it to people began recruiting in February 2026 and has reported no results.
That claim inverts the evidence, because exercise induces endogenous MOTS-c in human skeletal muscle and circulation. In a randomized study, endurance exercise raised humanin significantly while MOTS-c showed only a non-significant trend.
No. A meta-analysis found circulating MOTS-c significantly reduced in diabetes but significantly increased in obesity. A 2026 study found it higher in adults with obesity, and unchanged after bariatric surgery.
References
MOTS-c sits inside a mitochondrial gene whose job was never to make proteins. The discovery story, and what a sequence in a database does and doesn't prove.
PYY 3-36 research: human appetite infusion findings, a contested rodent replication record, dose-limiting nausea, and a Phase 2 trial that missed.
GDF-8 is myostatin, a negative regulator of muscle mass. No published or registered human study has given it to a person. Inhibitor data are separate.
Follistatin 344 is a protein, not a peptide. The five ClinicalTrials.gov studies using it as the intervention delivered a gene, not an injected protein.
ACE-031 is an ActRIIB-Fc fusion protein. Its Duchenne trial was stopped early for nosebleeds and telangiectasias, and it is approved nowhere.
An evidence-led review of PNC-27 research: the human record, FDA findings on material sold to patients, the proposed mechanism, and the cell and animal work.
An evidence-led review of FOXO4-DRI research: the proposed mechanism, the preclinical findings, the negative and null results, and the human record.
