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MOTS-c

MOTS-c is a small peptide made inside your own mitochondria. Your body produces less of it as you age, and exercise is the most reliable way to increase it naturally. Researchers have studied it for metabolic health, insulin sensitivity, and age-related decline. This page summarizes what the published literature reports about MOTS-c, what has been studied in humans, and where the evidence stops.

Compliance Notice: Important status notice. MOTS-c is not FDA approved for any therapeutic use. It was on the FDA Category 2 restricted list until 22 April 2026, when that designation was withdrawn. Its compounding status is pending FDA review. The only completed human trial used a modified version of MOTS-c developed by a company that has since discontinued operations. No Phase 1 safety trial has been completed for native MOTS-c.

WADA prohibition. MOTS-c was added to the WADA Prohibited List on January 1, 2024 under the S0 category (Non-Approved Substances) and appears on the 2025 list as an example under S4 (Hormone and Metabolic Modulators). It is prohibited at all times, in and out of competition, in every WADA-regulated sport. If you compete at any level in a WADA-regulated sport, MOTS-c is not appropriate for you. Do not use it.

Chemical structure diagram of the beta-lactam antibiotic Ceftriaxone showing carbon, hydrogen, nitrogen, oxygen, sulfur, and chlorine atoms.
Woman measuring her waist with a tape measure while wearing black workout clothes.Person in black workout clothes measuring their waist with a white and black tape measure.

Overview

MOTS-c is a peptide your mitochondria produce and release into circulation. It acts as a signaling molecule, telling the rest of your body (especially skeletal muscle) to take up glucose more efficiently and use energy better. It is one of the ways your mitochondria communicate with the rest of you, and it is part of why exercise improves metabolic health.

Two things about MOTS-c are unusually well characterized for a peptide this young in the literature. First, your blood levels of it decline with age, and patients with obesity and metabolic disease have lower levels than healthy controls. Second, exercise acutely raises both muscle and circulating MOTS-c, with skeletal muscle levels increasing nearly twelvefold during and after exertion. That is a clear biological story. As you get older and more sedentary, your own MOTS-c drops, and that drop tracks with metabolic decline.

The therapeutic idea is to supplement the peptide in patients whose endogenous signaling has fallen off. The idea is compelling. Human outcome data remains limited.

Man lifting dumbbells with focused expression in smoky gym lighting.

CHEMICAL STRUCTURE & PROPERTIES

  • Origin: Mitochondrial-derived peptide; encoded in the mitochondrial 12S rRNA
  • Amino Acid Length: 16 residues
  • Sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
  • Primary Target: AMPK (AMP-activated protein kinase)
  • Natural Trigger: Exercise; declines with age and metabolic disease
  • Route: Subcutaneous injection
  • Stability: Lyophilised powder; store at 2 degrees C to 8 degrees C before reconstitution
  • WADA Status: Prohibited -- S0 and S4 (2024 onward); not for competitive athletes

Mechanism of Action

MOTS-c exerts its metabolic effects through multiple interconnected mechanisms centered on mitochondrial signaling and glucose handling:

AMPK Activation

MOTS-c's primary mechanism runs through the same pathway as metformin, one of the most studied metabolic drugs in medicine:
  • MOTS-c activates AMPK (AMP-activated protein kinase), a master regulator of cellular energy balance
  • AMPK activation improves glucose uptake in skeletal muscle independent of insulin
  • This is the same pathway metformin activates, giving MOTS-c a well-characterized mechanistic anchor
  • AMPK activation also promotes fat oxidation and inhibits fat storage pathways

Skeletal Muscle Glucose Handling

Skeletal muscle is the primary site of MOTS-c action and the tissue most relevant to insulin resistance:
  • Exercise raises skeletal muscle MOTS-c levels nearly twelvefold during and after exertion
  • MOTS-c improves insulin sensitivity in skeletal muscle in animal models
  • It enhances glucose transporter activity, supporting non-insulin-dependent glucose uptake
  • Age-related decline in MOTS-c tracks directly with the loss of muscle metabolic flexibility

Mitochondrial Signaling and Energy Metabolism

MOTS-c acts as a communication signal from the mitochondria to the rest of the body:
  • It is produced inside mitochondria and released into circulation, making it a true mitochondrial hormone
  • Blood levels reflect the health and activity of your mitochondrial network
  • MOTS-c coordinates cellular responses to metabolic stress, including improved fat utilization
  • In animal models, MOTS-c preserves mitochondrial function and reduces age-related metabolic deterioration

Age-Related Metabolic Decline

The relationship between MOTS-c, aging, and metabolic disease is one of the best-characterized aspects of this peptide:
  • Circulating MOTS-c declines with age in humans and correlates with metabolic health markers
  • Patients with obesity and metabolic disease have lower MOTS-c levels than healthy controls
  • In aged animal models, MOTS-c administration restores metabolic profiles toward younger patterns
  • In high-fat-diet mouse models, MOTS-c prevented obesity and preserved metabolic flexibility

Areas Investigated in

the Research Literature

Insulin Resistance and Metabolic Health

Primary Investigation: Observational studies in humans confirm that circulating MOTS-c levels correlate with metabolic health markers and decline with age and metabolic disease.

  • Circulating MOTS-c levels are lower in patients with obesity, metabolic syndrome, and type 2 diabetes
  • In animal models, MOTS-c improves insulin sensitivity and glucose handling in skeletal muscle
  • AMPK activation by MOTS-c mirrors the mechanism of metformin, giving the pathway strong mechanistic credibility
  • The one human trial (CB4211, a modified analogue) met its Phase 1 safety endpoint and showed modest improvements in liver enzymes and glucose

Mechanism: MOTS-c activates AMPK in skeletal muscle, improving glucose uptake and insulin sensitivity through a pathway that does not require insulin itself -- directly addressing the muscle-level dysfunction driving insulin resistance.

Age-Related Metabolic Decline and Longevity

Emerging Applications: MOTS-c's role in aging and mitochondrial health has been studied in animals and observational human data over more than a decade.

  • MOTS-c levels decline with age in humans, tracking the loss of metabolic flexibility and muscle quality
  • In aged animal models, systemic MOTS-c restores metabolic profiles toward younger patterns
  • Cardiac function preservation has been demonstrated in animal models of aging
  • Exercise-related adaptations are enhanced by MOTS-c in preclinical models, suggesting a role in supporting training response

Mechanism: As a mitochondrial-derived signal that declines with age, MOTS-c supplementation attempts to restore the signaling environment that supports metabolic health -- addressing the drop in endogenous production that tracks with aging and sedentary behavior.

Metabolic Flexibility and Body Composition

Research Potential: Preclinical data on fat metabolism and body composition provides the basis for considering MOTS-c in patients with metabolic dysfunction, with appropriate expectations.

  • In high-fat-diet mouse models, MOTS-c prevented obesity without reducing food intake
  • MOTS-c promotes fat oxidation and inhibits fat storage pathways through AMPK
  • Lean body mass preservation has been observed in animal models alongside metabolic improvements
  • Effects on human body composition have not been established

Mechanism: AMPK activation shifts cellular metabolism toward fat utilization and away from fat storage, with downstream effects on body composition in animal models -- a finding that has not yet been replicated in human trials.

Man in black athletic wear leaning forward on an exercise bike against a dark background.

Current Clinical Evidence

Published Human Studies

The human data on MOTS-c is limited to observational studies and one Phase 1 trial of a modified analogue.

  • Observational studies confirm MOTS-c levels correlate with metabolic health and decline with age in humans
  • One Phase 1a/1b trial (CB4211, a modified MOTS-c analogue) enrolled 85 participants (healthy volunteers and NAFLD patients)
  • CB4211 met its primary safety endpoint; modest improvements in liver enzymes and glucose were observed
  • CB4211 did not complete Phase 2; the developing company (CohBar) has since discontinued operations

What the Research Has Not Yet Settled

The preclinical story is strong. The human clinical story is thin.

  • No completed Phase 1 safety or pharmacokinetic trial exists for native MOTS-c
  • The only human trial used a modified analogue developed by a company that no longer operates
  • Formal genotoxicity, carcinogenicity, and reproductive toxicity studies have not been conducted
  • Drug interaction data with insulin, GLP-1 agonists, and other glucose-lowering agents has not been formally studied

Research Limitations

Current evidence is constrained by:

  • Absence of a completed Phase 1 trial for native MOTS-c
  • Human efficacy data limited to a single Phase 1 trial of a modified analogue that did not reach Phase 2
  • All metabolic efficacy findings come from animal models and observational human studies
  • WADA prohibition limits athlete-population research and creates additional access constraints
  • The former FDA Category 2 classification reflected this evidence gap; it was withdrawn on 22 April 2026

Safety Considerations

Clinical Safety Data

The modified MOTS-c analogue CB4211 met its Phase 1 safety endpoint in a trial of 85 participants. Those are the best available human safety data.

  • No serious adverse events were reported in the CB4211 Phase 1 trial
  • The most common adverse event was injection site reaction related to the modified peptide's retention at the injection site
  • No hepatotoxicity or nephrotoxicity signal has appeared in preclinical studies of native MOTS-c
  • No cancer safety data exists

Theoretical Concerns

Potential considerations include:

  • No completed Phase 1 trial for native MOTS-c; formal pharmacokinetic, genotoxicity, and carcinogenicity data are absent
  • Additive glucose-lowering risk in patients on insulin, GLP-1 agonists, or other glucose-lowering agents has not been formally studied
  • No cancer safety data; MOTS-c is not used in patients with active or previously treated malignancy
  • Long-term repeated-dose safety in humans is not characterized

Contraindications

Populations excluded from published studies, and where use would be contraindicated:

  • Anyone competing in a WADA-regulated sport at any level (prohibited, no exceptions)
  • Avoid in active or previous cancer unless specifically cleared by the treating clinician.
  • Pregnancy, planned pregnancy, or breastfeeding
  • Use caution with insulin, GLP-1 medications, and other blood-sugar-lowering treatments because MOTS-c is discussed in relation to glucose handling/metabolic pathways.
  • Anyone whose case has not been reviewed by a qualified clinician familiar with their full history

Regulatory Status and Legal Considerations

Regulatory information current as of 28 August 2026. This is a summary, not legal or medical advice, and status can change.

FDA Status

No Approved Medical Use:
  • MOTS-c is not FDA approved for any therapeutic indication
  • MOTs-C was previously on the FDA Category 2 restricted list. As of April 22, 2026, it is listed as Nominated but Withdrawn from Category 2
  • On 23-24 July 2026, the FDA Pharmacy Compounding Advisory Committee recommended MOTS-c for the 503A bulk drug substances list. The recommendation is advisory and non-binding; formal listing is still pending.

WADA Status

Prohibited Substance Classification:
  • MOTS-c was added to the WADA Prohibited List on January 1, 2024 under S0 (Non-Approved Substances)
  • It also appears on the 2025 list as an example under S4 (Hormone and Metabolic Modulators, AMPK activator category)
  • Prohibited at all times, in and out of competition, in every WADA-regulated sport
  • MOTS-c is prohibited under WADA. Athletes in WADA-regulated sport should not use it from any source

Legal Availability

Legal and Regulatory Status:
  • Research use of MOTS-c is legal in the United States for non-competing adults
  • It is not approved as a therapeutic, which is a different question from legality
  • Products sold outside licensed channels carry sterility and purity risks that no authority audits
Person gripping a black dumbbell from a rack in a gym setting with wooden wall background.

Conclusion

What the evidence supports

MOTS-c is a mitochondrial-derived peptide with a genuinely interesting mechanism: it appears to act as a signal from the mitochondrial genome to the nucleus, influencing metabolic regulation under stress. Animal work has reported improved insulin sensitivity and exercise capacity.

The human evidence has not followed. Effects on body composition have not been established in people, no cancer safety data exists, and dosing has not been standardized. MOTS-c is not FDA approved and is prohibited under WADA. This page summarizes the published research and nothing further.

MOTS-c SCIENTIFIC

DATA SUMMARY

Parameter
Value
Full Name
Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c)
Peptide Structure
16-amino acid peptide: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR)
Molecular Formula
C₁₀₁H₁₅₂N₂₈O₂₂S₂
Molecular Weight
2,174.6 Da
CAS Number
1627580-64-6
PubChem CID
146675088
Genomic Origin
Encoded by a 51-base-pair short open reading frame (sORF) within the mitochondrial 12S rRNA gene (MT-RNR1); translated in the cytoplasm using the standard genetic code (not the mitochondrial code); polyadenylated transcript exported from mitochondria prior to translation
Discovery
First identified in 2015 by Lee et al. (Cell Metabolism, PMID 25738459) via in silico sORF screening of human 12S rRNA; first mitochondrial peptide known to translocate to the nucleus
Sequence Conservation
First 11 residues (MRWQEMGYIFY) highly conserved across 14 species including humans and mice; positive selection confirmed by dN/dS ratio analysis
Endogenous Expression
Co-localizes to mitochondria in numerous tissues (brain, heart, liver, skeletal muscle, testes, kidney, spleen, intestine); circulates in plasma of both rodents and humans; levels decline with age — circulating MOTS-c is higher in young adults than in middle-aged and older adults (70–81 years)
Exercise Response
Exercise Response: Endogenous skeletal-muscle MOTS-c increased approximately 11.9-fold following exercise in a small human study and remained elevated in muscle for up to 4 hours. Circulating MOTS-c also increased during and after exercise. These findings describe endogenous exercise physiology and should not be interpreted as evidence that exogenous MOTS-c therapy produces the same effect.
Chemical Stability
Reconstituted in water: stable with no significant degradation for ≥30 days at 4°C (confirmed by high-resolution MS tracking methionine oxidation). Lyophilized powder: stable long-term at −20°C. Contains two methionine residues susceptible to oxidation — primary degradation marker
Half-Life
Biological half-life in humans not formally established. Estimated 1–2 hours based on exercise-induced circulating level kinetics (return to baseline within 4h). In vivo exogenous half-life likely short; duration of biological activity exceeds circulating half-life due to intracellular and nuclear mechanisms
Bioavailability
Subcutaneous injection primary route in preclinical research. Oral and intraperitoneal routes used in animal studies. Oral bioavailability in humans not established. Low oral bioavailability, poor stability, and short half-life identified as key clinical development challenges. Cell-penetrating analogue (CB4211) developed to improve delivery
Pathway
Effect
AMPK Activation (Primary)
Inhibits the folate cycle at the level of 5-methyltetrahydrofolate (5Me-THF), disrupting the tethered de novo purine biosynthesis pathway; this causes accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), a potent endogenous AMPK activator. AICAR → AMPK activation → improved glucose uptake and fatty acid oxidation in skeletal muscle. This mechanism distinguishes MOTS-c from metformin (which acts primarily on liver) and targets skeletal muscle as primary site of action
Nuclear Translocation
Under metabolic stress, MOTS-c translocates from mitochondria to nucleus in an AMPK-dependent manner; requires hydrophobic interactions (possibly involving chaperone proteins); binds to ARE (Antioxidant Response Element)-regulated transcription factors to regulate nuclear gene expression including GLUT4, STAT3, IL-10, PGC-1α, and NRF2-regulated genes; improves cellular stress resistance
Insulin Sensitivity / GLUT4
AMPK activation upregulates GLUT4 (glucose transporter type 4) expression and membrane translocation in skeletal muscle; activates the Akt pathway in muscle cells; improves insulin-stimulated glucose disposal (70–85% of postprandial glucose disposal occurs in skeletal muscle); reverses age-related and HFD-induced insulin resistance
Anti-Inflammatory Signaling
AMPK activation inhibits MAP kinase (ERK, JNK, P38) and c-Fos expression; reduces pro-inflammatory cytokines; increases anti-inflammatory cytokines (e.g., IL-10); inhibits NF-κB activation; reduces NLRP3 inflammasome activation (via ROS/TXNIP/NLRP3 pathway modulation in cardiac tissue)
Mitochondrial Protection / NRF2
MOTS-c/NRF2 interaction upregulates mitochondrial protective gene expression; restores mitochondrial respiration and ATP content in senescent and diabetic cells; promotes mitochondrial biogenesis (via PGC-1α, tFAM); reduces reactive oxygen species; activates SIRT1 downstream of AMPK
Cardiovascular Protection
Activates AMPK pathway in cardiomyocytes; activates NRG1-ErbB4 and NRG1/ErbB4/CEBPβ pathways to restore cardiac function; inhibits CCN1/ERK1/2/EGR1 pathway to repair myocardial damage; reduces oxidative stress and apoptosis in cardiac cells; mitofusion required for MOTS-c-induced GLUT4 translocation in cardiomyocytes
Bone / Immune Effects
Inhibits osteolysis by modulating osteocyte-osteoclast crosstalk and suppressing local inflammation (Yan et al., Pharmacol Res 2019); prevents pancreatic islet destruction in autoimmune diabetes by preserving β-cell function (Kong et al., Cell Rep 2021); anti-MRSA activity demonstrated in murine infection model (Zhai et al., Mol Immunol 2017)
Genetic Association / Longevity
MOTS-c gene polymorphisms (particularly K14Q variant in mtDNA) associated with human longevity in population studies (Fuku et al., Aging Cell 2015); K14Q polymorphism also associated with muscle fiber composition and muscular performance; constitutes a pro-diabetogenic mtDNA variant in some populations (Zempo et al., 2021)
Application
Model
Dose / Route
Reported outcome (model)
Insulin Resistance / HFD Obesity
CD-1 mice on high-fat diet (Lee et al. 2015, Cell Metab, PMID 25738459)
Various doses SC; 15 mg/kg used in key studies (animal/preclinical)
Prevented HFD-induced obesity and hyperinsulinemia; improved glucose tolerance; restored insulin sensitivity to levels comparable with normal-diet controls; no effect on body weight in normal-diet mice; GLUT4 upregulation confirmed as mechanism
Age-Related Insulin Resistance
Aged male mice (Lee et al. 2015; Guo et al. 2020)
Various doses SC × 7 days (animal/preclinical)
Insulin sensitivity of old mice restored to levels equivalent to young mice after 7 days of MOTS-c intervention; increased glucose uptake in soleus muscles; reversed age-dependent reduction in MOTS-c levels in skeletal muscle and blood
Age-Related Physical Decline
Aged mice (Reynolds et al. 2021, Nat Commun 12:470, PMID 33473109)
15 mg/kg SC (animal/preclinical)
Systemic MOTS-c administration reversed age-dependent physical decline; improved grip strength, treadmill endurance, and muscle homeostasis; regulated transcriptional programs linked to muscle aging; MOTS-c described as exercise-induced regulator of age-dependent decline
Cardiovascular / Heart Failure
Pressure-overload heart failure model (mice); diabetic rat cardiac models (Zhong et al. 2022; Li et al. 2022; Yuan et al. 2021)
0.5–5 mg/kg SC or IP (animal/preclinical)
Prevented heart failure development under pressure overload via AMPK activation; restored cardiac function in diabetic rats via NRG1-ErbB signaling; improved myocardial performance during exercise training; reduced left ventricular wall thickening; repaired myocardial damage via CCN1/ERK1/2/EGR1 inhibition
Type 1 and Gestational Diabetes
STZ-induced T1D mice and rats; gestational diabetic mice (Yin et al. 2022; Kong et al. 2021)
10 mg/kg IP or SC (animal/preclinical)
Reduced hyperglycemia; improved insulin resistance in gestational diabetes mellitus; prevented pancreatic islet destruction in autoimmune (NOD mouse) T1D; restored blood glucose levels in STZ-diabetic animals; preserved β-cell mass
Inflammation / Analgesia
Murine formalin test (Yin et al. 2020, Eur J Pharmacol 870:172909)
Intraperitoneal injection, dose-dependent (animal/preclinical)
Dose-dependent reduction in licking time (phase 2 of formalin test); significant decrease in pro-inflammatory cytokines; increase in anti-inflammatory cytokines; effect blocked by AMPK antagonist Compound C, confirming AMPK-dependence; inhibited ERK, JNK, P38, and c-Fos activation
Postmenopausal Metabolic Dysfunction
Ovariectomized mice (Lu et al. 2019, J Mol Med)
Various doses SC (animal/preclinical)
Partially reversed ovariectomy-induced obesity and insulin resistance; increased adipose thermogenic activation; regulated adipose homeostasis; MOTS-c levels decline with estrogen withdrawal, consistent with hormone-peptide crosstalk
T2D Cardiac Mitochondrial Function
Streptozotocin + high-fat diet T2D rats (2025, PMC12257629)
0.5 mg/kg SC × 8–12 weeks (animal/preclinical)
Restored mitochondrial respiration per tissue mass; improved citrate synthase activity; decreased fasted blood glucose; reduced left ventricular wall thickness 8%; increased mitochondrial biogenesis markers (PGC-1α, tFAM); improved AMPK signaling and GLUT4 expression in skeletal muscle
MOTS-c Analogue (CB4211) — NAFLD
Diet-induced obesity mouse model; STAM™ NAFLD mouse model (CohBar, preclinical)
5 or 15 mg/kg IP BID × 21 days (animal/preclinical)
Reduced body weight and liver steatosis; greater fat-loss specificity than liraglutide; reduced NAFLD Activity Score (15 mg/kg); reduced liver triglycerides and plasma ALT; led to Phase 1a/1b human trial (NCT03998514)
Study Type
Population
Results
Limitations
CB4211 Phase 1a/1b Trial (NCT03998514)
20 obese adults with ≥10% liver fat; 11 treated (25 mg CB4211 SC once daily), 9 placebo × 28 days (CohBar Inc., 2021)
Met primary safety endpoint; CB4211 is a MOTS-c analogue, not native MOTS-c itself; topline results released 2021; CohBar subsequently discontinued operations — full data not published in peer-reviewed journal
Small sample size (n=20); only 28-day duration; CB4211 ≠ native MOTS-c; no published peer-reviewed efficacy data; company discontinued; no Phase 2 follow-up
Observational / Cross-Sectional: Plasma MOTS-c vs. Metabolic Markers
Multiple human cohort studies including obese Chinese male children/adolescents (5–14 years, n=various); adult men (31–38 years); older adults (70–81 years)
Obese boys/adolescents had significantly lower circulating MOTS-c; plasma MOTS-c in men negatively correlated with fasting insulin, HbA1c, and BMI; 70–81-year-olds had lower MOTS-c than 18–30-year-olds; no correlation with BMI found in 31–38-year-old cohort (contradictory result)
Observational only — no intervention; contradictory BMI findings between age cohorts; small sample sizes; correlational data cannot establish causality; confounded by individual variation
Exercise Studies (Human)
Healthy adults (Reynolds et al. 2021, Nat Commun; Hyatt 2022, Physiol Rep)
Exercise increases skeletal muscle MOTS-c 11.9-fold vs. pre-exercise; persists 4h post-exercise. Circulating MOTS-c +1.6-fold during, +1.5-fold after exercise; returns to baseline within 4h. Long-term exercise training increases skeletal muscle MOTS-c and improves acute exercise performance after single exogenous dose. Single dose improved performance in trained subjects (Hyatt 2022)
Small sample sizes; not a therapeutic trial; performance effects of exogenous dosing based on limited data; confounded by exercise protocol variation
Overall Clinical Evidence Level
N/A
No completed, peer-reviewed Phase 2 or Phase 3 therapeutic trials for native MOTS-c in any indication. Closest human trial used a modified analogue (CB4211) and was not fully published. Endogenous MOTS-c levels are robustly correlated with metabolic health in observational studies. Preclinical therapeutic evidence is extensive but not translated to human trials.
No FDA-approved or investigational new drug (IND) application known for native MOTS-c. Major translational barriers: short half-life, low oral bioavailability, poor stability, difficulty penetrating cells without degradation, and absence of a well-defined receptor. Comprehensive clinical development has not begun.
Parameter
Finding
Acute Tolerability
No acute toxicity observed in preclinical studies across multiple species and routes; CB4211 analogue met primary safety endpoint in Phase 1a/1b human trial (n=20, 28 days)
Endogenous Context
MOTS-c is a naturally occurring mitochondrial-derived peptide present in all humans and rodents from birth; endogenous levels positively correlate with metabolic health markers, providing some baseline safety context for physiological concentrations
Metabolic Safety
No evidence of hypoglycemia in animal models even at high doses; does not impair glucose tolerance; does not affect body weight in normal-diet animals; no hepatotoxicity (unlike metformin, AICAR, or methotrexate — which all activate AMPK but have liver toxicity profiles)
Sex Effects
MOTS-c shows a documented sex effect — levels more heavily impacted by metabolic status in males than females in some studies; ovariectomy (estrogen withdrawal) reduces MOTS-c and worsens metabolic function; sex-specific dosing effects not fully characterized
Immunogenicity
No immunogenicity events published in preclinical literature; as an endogenous human peptide, immunogenic risk is theoretically lower than for foreign proteins; however, no formal immunogenicity testing per ICH standards has been conducted for exogenous administration
Potential Maladaptive Risk
In longevity model organisms, excessive mitochondrial stress buffering may reduce the beneficial mitohormetic response (cellular "toughening" via mild stress); it has not been established whether excess MOTS-c supplementation could become maladaptive — a theoretical concern without established evidence in mammals
Long-term Safety
No long-term human safety data; no formal toxicology studies (genotoxicity, carcinogenicity, reproductive toxicity) per ICH guidelines conducted for native MOTS-c; chronic effects unknown; no dose-escalation Phase 1 safety trial completed for native peptide
Drug Interactions
No published drug interaction studies; primary mechanism (AMPK activation) overlaps with metformin — combined use may theoretically produce additive effects; pharmacodynamic interactions with other AMPK modulators, insulin sensitizers, or exercise-inducing protocols not formally studied
Route
Application
Notes
Subcutaneous Injection
Insulin resistance, aging, exercise mimetic, cardiovascular, metabolic
Primary route in most preclinical studies; doses range 0.5–15 mg/kg depending on model and duration; longer treatment periods (8–12 weeks) use lower doses (0.5–5 mg/kg); shorter periods (2–4 weeks) use higher doses (10–15 mg/kg)
Intraperitoneal Injection
Inflammation / analgesia; NAFLD (CB4211)
Used in formalin pain/inflammation model; CB4211 analogue used IP BID in NAFLD mouse model; common route in acute rodent pharmacology studies
Oral Administration
IBD-related inflammation (MOTS-c analogue, investigational)
An orally administered MOTS-c analogue ameliorated DSS-induced colitis in mice by inhibiting inflammation and apoptosis (Jiang et al., Eur J Pharmacol 2023). Native MOTS-c oral bioavailability in humans not established; poor stability in GI tract is a key limitation for native peptide
Cell-Penetrating Analogues
NAFLD, metabolic disease (CB4211, CohBar)
CB4211 is a modified MOTS-c analogue with enhanced cell penetration; 25 mg SC once daily used in Phase 1a/1b trial; CohBar discontinued operations post-trial — development status uncertain
Synthetic Biology / Engineered Bacteria
Investigational delivery platform
Proposed approach: introducing MOTS-c gene into probiotic bacteria (e.g., Lactobacillus, E. coli Nissle1917) for precise, controllable gut expression; remains preclinical concept only; challenges include bacterial virulence, uncontrolled immune response, and biosafety concerns
Authority
Classification
Status
FDA (USA)
Formerly Category 2 (503A list); designation withdrawn 22 April 2026
Not approved for any human therapeutic indication. Previously placed on the FDA Category 2 list (late 2023–2024); that designation was withdrawn on 22 April 2026. Removal from Category 2 does not make MOTS-c eligible for compounding — standard 503A/503B pharmacy regulations now apply pending further FDA action.
WADA
S0 — Non-Approved Substances; Prohibited at All Times
Explicitly added to the WADA Prohibited List effective January 1, 2024 (2024 List, S0 category). WADA noted MOTS-c is "heavily marketed by wellness and anti-aging clinics as a weight loss peptide" despite not being approved for human therapeutic use. Prohibited in all sports, both in- and out-of-competition. Athletes testing positive face sanctions.
EU / UK
Unapproved; research use only
Not approved by EMA or MHRA for any indication; available only as unregulated research chemical
Australia (TGA)
Unapproved substance
Not approved for therapeutic use; cannot be prescribed or sold for clinical use without specific TGA authorization
Research Use
Investigational research compound
Available as research-grade peptide from suppliers; intended for laboratory use only; pharmaceutical-grade compounding currently restricted in the US pending formal FDA reclassification. No IND application for native MOTS-c known to be active.
Pharmaceutical Development
Preclinical / No completed therapeutic trials for native peptide
No Phase 2 or Phase 3 trials for native MOTS-c in any jurisdiction. CB4211 analogue (CohBar) completed Phase 1a/1b (NCT03998514) for NAFLD but company discontinued. Key development barriers: short half-life, poor oral bioavailability, cell penetration challenges, and undefined receptor. Active academic research ongoing globally — metabolic disease, aging, and cardiovascular primary focus areas.

About this library

This library is published for education. It summarizes published research on compounds studied in this field. Many have no approved medical use, and several cannot lawfully be compounded in the United States. The presence of a page here does not mean Paragon offers that compound. Nothing on these pages is an offer to treat.

This page is general education about a compound studied in this field. Nothing here is medical advice, a recommendation, or an offer to prescribe or supply. A page appearing in this library does not mean Paragon Sports Medicine offers that compound.

Disclaimer: This information is provided for educational purposes only and does not constitute medical advice. MOTS-c is not FDA approved for any therapeutic indication and had its Category 2 designation withdrawn on 22 April 2026; that withdrawal does not itself authorize compounding, and its 503A status remains pending FDA action. MOTS-c is prohibited under WADA S0 and S4 categories and must not be used by anyone competing in a WADA-regulated sport at any level. Patients should consult with a qualified clinician and ensure regulatory compliance before considering any use of MOTS-c.

Statements on this page have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease. Many peptides described here are not FDA approved for the uses discussed, and some cannot lawfully be compounded in the United States. Nothing on this page is medical advice or a recommendation for any individual. Whether any therapy is appropriate depends on your history, your laboratory results, and a clinical evaluation. Individual results vary. This page is published for education. Use of this site does not create a physician-patient relationship.

References

01
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015.
02
MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol. 2023.
03
MOTS-c Functionally Prevents Metabolic Disorders. Metabolites. 2023.
04
MOTS-c: A Mitochondrial-Encoded Regulator of the Nucleus. Bioessays. 2019.
05
MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016.