tuneTypical Dose
5 mg/kg/day (preclinical reference), 0.5 mg/kg/day to 15 mg/kg/day (preclinical reference ranges)
Peptide
MOTS-c
mitochondrial open-reading-frame of the 12S rRNA-c
Evidence TierCWADA PROHIBITED
watchEffect Window
Animal data show changes over several days to weeks. Human effects limited to acute biomarker response in exercise settings.
lockCompliance
WADA PROHIBITED
Overview
Clinical Summary
MOTS-c is a mitochondrial-derived peptide studied for metabolic regulation and exercise adaptation. It is discussed for insulin sensitivity and endurance-related outcomes, but human clinical data remain minimal.
Animal studies suggest improved insulin sensitivity, increased fat oxidation, and enhanced exercise capacity through AMPK-related pathways. Human evidence is limited to early biomarker work, so practical benefits are unproven. Minority claims include anti-inflammatory and longevity effects, largely speculative. Safety, dosing, and long-term outcomes are not well established, limiting confidence in real-world benefit.
AMPK-linked mitochondrial-to-nuclear metabolic signaling in muscle. Promotes glucose-handling and adaptation pathways in preclinical settings.
Outcomes
What This Is Expected To Influence
Primary Outcomes
- Insulin sensitivity proxies
- Metabolic adaptation markers
Secondary Outcomes
- Exercise biomarker responsiveness
- Body composition-related mouse outcomes
Safety
Contraindications and Interactions
Contraindications
- Pregnancy
- Breastfeeding
- Pediatric use
- Severe endocrine/cardiometabolic instability
- Uncontrolled psychiatric risk
Side effects
- Injection site reactions
- Limited human safety data
Interactions
- Potential glucose-lowering interaction risk with antidiabetic regimens (theoretical/metabolic pathway overlap)
- Potential overlap with other AMPK or metabolic modulators
Avoid if
- Athletic competition risk without clearance
- Self-directed stacking
- Unstable cardiac rhythm
- Liver dysfunction with active protocol involvement
Evidence
Study-level References
mots-c-SRC-001Preclinical (mice)
Sourceopen_in_newLee C. et al., Cell Metabolism 2015 (PMID: 25738459, DOI: 10.1016/j.cmet.2015.02.009); https://pubmed.ncbi.nlm.nih.gov/25738459/
Population: C57BL/6 and CD-1 mice, high-fat-fed and age-variant cohorts
Dose protocol: 5 mg/kg/day IP for 7 days. 0.5 mg/kg/day IP for up to 8 weeks
Key findings: Improved insulin sensitivity and glucose handling, prevented aspects of age/HFD insulin resistance, reduced HFD weight gain in mice.
Notes: Strong mechanistic signal and dose-response clarity in rodents. No direct human efficacy inference.
Paper content
Improved insulin sensitivity and glucose handling, prevented aspects of age/HFD insulin resistance, reduced HFD weight gain in mice.
mots-c-SRC-002Preclinical + human biomarker arm
Sourceopen_in_newReynolds J. C. et al., Nature Communications 2021 (PMID: 33473109, DOI: 10.1038/s41467-020-20790-0); https://pubmed.ncbi.nlm.nih.gov/33473109/
Population: Young/middle-age/old mice; 30 healthy young men in acute exercise sampling
Dose protocol: Mice: 5 or 15 mg/kg/day IP for 2 weeks (performance study), including late-life intervention with intermittent 3x/week dosing windows. Humans: acute bicycle exercise challenge with blood/muscle sampling pre/post exercise.
Key findings: MOTS-c improved mouse performance and metabolic outcomes. Humans showed transient exercise-induced increases in circulating and muscular MOTS-c.
Notes: Human component was biomarker-only, not a dosing trial. Small sample limits external validity.
Paper content
MOTS-c improved mouse performance and metabolic outcomes; humans showed transient exercise-induced increases in circulating and muscular MOTS-c.
mots-c-SRC-003Randomized controlled trial (human acute intervention)
Sourceopen_in_newvon Walden F. et al., J Appl Physiol 2021 (PMID: 34351816, DOI: 10.1152/japplphysiol.00706.2019); https://pubmed.ncbi.nlm.nih.gov/34351816/
Population: Healthy adults (n=30), endurance/resistance exercise arms
Dose protocol: Acute 45 min endurance cycling or resistance protocol. Plasma and muscle sampling at baseline/30 min/3 h.
Key findings: Endurance exercise increased MOTS-c trend/signals in humans. No direct therapeutic intervention dosing established.
Notes: Useful for biological plausibility, not clinical outcome demonstration.
Paper content
Endurance exercise increased MOTS-c trend/signals in humans; no direct therapeutic intervention dosing established.
mots-c-SRC-004Cross-sectional human study
Sourceopen_in_newD’Souza R. et al., Aging (Albany NY) 2020 (PMID: 32182209, DOI: 10.18632/aging.102944); https://pubmed.ncbi.nlm.nih.gov/32182209/
Population: Healthy aging men
Dose protocol: Observational plasma and skeletal muscle sampling only
Key findings: Plasma MOTS-c declined with age. Skeletal muscle MOTS-c higher in older groups versus young men, with muscle-quality associations.
Notes: Association-based signal with no intervention dosing.
Paper content
Plasma MOTS-c declined with age; skeletal muscle MOTS-c higher in older groups versus young men, with muscle-quality associations.
mots-c-SRC-005Observational human study
Sourceopen_in_newCataldo L. et al., J Investig Med 2018 (PMID: 29593067, DOI: 10.1136/jim-2017-000681); https://pubmed.ncbi.nlm.nih.gov/29593067/
Population: Lean vs obese adults (n=10 per group)
Dose protocol: Fasting baseline plasma biomarker measurements
Key findings: MOTS-c levels were not significantly different between lean and obese adults in this small sample. Correlations with IR markers differed by group.
Notes: Confirms context-dependent associations but not causal treatment effects.
Paper content
MOTS-c levels were not significantly different between lean and obese adults in this small sample; correlations with IR markers differed by group.
mots-c-SRC-006Case-control human study
Sourceopen_in_newDu C. et al., Pediatr Diabetes 2018 (PMID: 29691953, DOI: 10.1111/pedi.12685); https://pubmed.ncbi.nlm.nih.gov/29691953/
Population: Obese and healthy children/adolescents
Dose protocol: Plasma MOTS-c assays at baseline
Key findings: Lower MOTS-c in obese male youth and stronger correlations with BMI and IR markers in that subgroup.
Notes: Suggests possible biomarker relevance in pediatric obesity context.
Paper content
Lower MOTS-c in obese male youth and stronger correlations with BMI and IR markers in that subgroup.
mots-c-SRC-007Regulatory guidance/educational source
Sourceopen_in_newUSADA "What is MOTS-c?" guidance page: https://www.usada.org/spirit-of-sport/what-is-mots-c-peptide/
Population: Athletes and public users
Dose protocol: N/A
Key findings: States no FDA approval for human use, experimental status, no completed clinical trials cited in this context, WADA 4.4.1 prohibition under AMPK activators, and no approved dietary/supplement pathway.
Notes: Not a peer-reviewed efficacy source. Useful for governance and risk controls.
Paper content
States no FDA approval for human use, experimental status, no completed clinical trials cited in this context, WADA 4.4.1 prohibition under AMPK activators, and no approved dietary/supplement pathway.
mots-c-SRC-008Clinical trial (Phase 1, investigational analog)
Sourceopen_in_newCohBar CB4211 phase 1a/1b clinical registry program (NCT03998514): https://clinicaltrials.gov/study/NCT03998514
Population: Healthy adults and adults with NAFLD
Dose protocol: Single- and multiple-ascending subcutaneous doses, multiple 7-day and 28-day PK/safety windows
Key findings: Supports that analog-stage human studies are early, PK/safety-focused only in limited settings.
Notes: Not directly equivalent to native MOTS-c, endpoint set not designed as broad efficacy validation.
Paper content
Supports that analog-stage human studies are early, PK/safety-focused only in limited settings.
mots-c-SRC-009Anti-doping standard reference
Sourceopen_in_newhttps: //www.usada.org/spirit-of-sport/what-is-mots-c-peptide/
Population: All competition contexts where WADA list applies
Dose protocol: N/A
Key findings: MOTS-c explicitly enumerated in the AMPK activator example set, reinforcing anti-doping governance status.
Notes: Governance source only, not a clinical efficacy source.
Paper content
MOTS-c explicitly enumerated in the AMPK activator example set, reinforcing anti-doping governance status.
mots-c-SRC-010Randomized controlled trial.
Sourceopen_in_newElhusseiny R, Ihsan M, Labidi M, et al. Repeated heat stress modulates the levels of the mitokines MOTS-C and FGF21 in active men during calf muscle immobilization. Med Sci Sports Exerc. 2025;57(12):2764-2774. doi:10.1249/MSS.0000000000003825. PMID:40674654.
Population: Physically active men undergoing calf muscle immobilization.
Dose protocol: 4 weeks supervised training followed by 2 weeks calf immobilization with repeated heat stress vs sham
Key findings: Repeated heat stress upregulated circulating MOTS-c (P=0.033). Immobilization alone did not affect levels.
Notes: First human RCT showing a non-exercise stimulus modulates endogenous MOTS-c. Biomarker outcome only.
Paper content
This randomized controlled trial examined whether repeated heat stress could modulate mitokine levels in physically active men during a period of calf muscle immobilization. Nineteen men completed 4 weeks of supervised training followed by 2 weeks of ankle immobilization, with randomization to heat treatment or sham. Heat stress significantly upregulated circulating MOTS-c (P=0.033), while immobilization alone did not affect mitokine levels. This is one of the first human RCTs to show that a non-exercise stimulus (heat) can modulate endogenous MOTS-c levels. The finding supports the biological plausibility of MOTS-c as a stress-responsive mitokine in humans, although the study measured biomarker levels rather than downstream metabolic or performance outcomes.