Research Dossier on Mots-C

(Mitochondrial Peptide)

Classification & Molecular Identity

Amino-acid sequence, molecular weight, structural motifs

MOTS-c is a 16-amino-acid peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Met-Gln-Gly-Ser-Thr-Gln-Glu-Lys-Ser in human; sometimes reported in single-letter as MRWQEMGMMQGQGNRK with minor sequence reporting differences depending on orthology/notation) that is translated from a short open reading frame (sORF) within the mitochondrial 12S rRNA gene (MT-RNR1). It was first functionally characterized in 2015 as a mitochondria-derived peptide (MDP)with metabolic regulatory properties.Cell

MOTS-c is stress-responsive—it is acutely induced by metabolic stressors and certain forms of exercise, and in cells can translocate from cytoplasm to the nucleus where it binds chromatin and helps coordinate nuclear gene expression programs. Nuclear translocation is facilitated by stress-activated pathways that reveal a cryptic nuclear localization signal and enable MOTS-c to engage antioxidant response element (ARE)-containing gene networks.PMC+1

Discovery history (lab, year, species)

The modern discovery lineage dates to 2015, when Lee et al. reported that MOTS-c is encoded by the mitochondrial genome and functions as a metabolic regulator in mice and human cells, notably improving insulin sensitivity and shifting substrate use via the folate–purine–AMPK axis (see Mechanisms).Cell Subsequent work (2018) demonstrated stress-induced nuclear translocation and transcriptional control, positioning MOTS-c as a peptide mediator of retrograde mitochondria-to-nucleus signaling.PMC Human observational and experimental studies (2020–2022) linked MOTS-c to aging biology and exercise adaptation, and a 2021 study established exercise-induced MOTS-c in humans and mice.Aging-US+1

Endogenous vs synthetic origin

• Endogenous: MOTS-c is mitochondrially encoded and produced endogenously in mammals. Circulating levels vary with age and physiological stress, and skeletal muscle expression increases with long-term training despite a decline in plasma levels with age.Aging-US+1

• Research material: Synthetic MOTS-c (or analogues) is used in preclinical studies; a first-in-human program employed a MOTS-c analogue (CB4211) rather than native MOTS-c. (See Human Clinical Evidence.)GlobeNewswire

Homologs, analogs, derivatives

• Other MDPs: Humanin, small humanin-like peptides (SHLPs)—mitochondria-encoded peptides with cytoprotective/metabolic roles.

• CB4211: A MOTS-c analogue developed by CohBar; advanced through a Phase 1a/1b safety and exploratory pharmacodynamics program for NASH/obesity (company-reported results; native MOTS-c was not tested).GlobeNewswire+1

Historical Development & Research Trajectory

Key milestones in discovery and study

• 2015 — Functional identification: MOTS-c is reported to improve insulin sensitivity, enhance glucose handling, and prevent diet-induced obesity in mice via a distinctive folate–purine–AMPK pathway (see below). Investigational dose used in study: 0.5 mg·kg⁻¹·day⁻¹ in HFD-fed mice (i.p. for 3 weeks).PMC

• 2018 — Nuclear translocation: Under stress, MOTS-c translocates to the nucleus and modulates ARE-containing stress-response genes, linking mitochondrial peptides to chromatin-level control.PMC

• 2020–2021 — Aging & exercise: Circulating MOTS-c declines with age; skeletal muscle MOTS-c rises with long-term training, and exercise acutely increases skeletal muscle/blood MOTS-c, with performance benefits reported in mice across age groups.Aging-US+2PMC+2

• 2021–2024 — Disease models: Protective effects reported across models (e.g., autoimmune diabetes, NASH-diet liver injury, radiation-induced pneumonitis), generally aligning with AMPK activation, inflammation dampening, and proteostasis support.PMC+2ScienceDirect+2

• 2019–2021 — First-in-human analogue: CB4211 enters Phase 1a/1b. Company communications report tolerability and reductions in ALT/AST and glucose versus placebo over 4 weeks in overweight adults with elevated liver enzymes. (Exploratory biomarkers; not native MOTS-c.)GlobeNewswire

Paradigm shifts and controversies

1. Mitochondrial peptides as hormones: MOTS-c helped establish the MDP concept—mitochondria encode bioactive peptides that act locally and systemically, with retrograde signaling to the nucleus—a notable expansion of mitochondrial biology.PMC

2. From metabolism to healthspan: Beyond insulin sensitization, studies tie MOTS-c to exercise capacity, proteostasis, cellular stress resistance, and potential healthspan effects in mice—promising, yet translation to humans is incomplete.Nature

3. Clinical evidence gap: Native MOTS-c lacks completed, peer-reviewed human efficacy trials; analogue (CB4211) data are early-phase and company-reported. Safety and pharmacokinetics in humans remain Not established for MOTS-c.GlobeNewswire+1

Evolution of scientific interest

Initial focus on metabolic regulation broadened to aging, exercise physiology, immune modulation, islet senescence, muscle atrophy, liver disease, and bone metabolism—often converging on AMPK and stress-adaptationpathways.BioMed Central+2PMC+2

Mechanisms of Action

Primary and secondary receptor interactions

No classical cell-surface receptor for MOTS-c has been definitively identified. Instead, the most consistent evidence supports intracellular actions:

• Transport/entry: MOTS-c is a small, cationic peptide; cells internalize it under stress or via yet-to-be-fully defined uptake mechanisms. After stress exposure, MOTS-c relocates to the nucleus and binds chromatin.PMC

• Metabolic axis: MOTS-c modulates one-carbon (folate) and purine biosynthesis, causing AICAR accumulation—a known AMPK agonist—thereby activating AMPK and downstream metabolic programs (↑ fatty-acid oxidation, ↑ glucose uptake, ↑ mitochondrial biogenesis genes).Cell+1

• Exercise/aging axis: MOTS-c regulates nuclear genes linked to metabolism, proteostasis, and stress adaptation, coordinating responses that enhance physical performance in mice and are induced by exercise in humans.Nature

Bottom line: The field currently views MOTS-c as a stress-adaptive mitokine that activates AMPK (via folate-purine-AICAR) and reprograms nuclear transcription during metabolic stress; a dedicated membrane receptor remains Unknown.BioMed Central

Intracellular signaling pathways

• Folate–purine–AICAR–AMPK: Suppression of de novo purine biosynthesis and folate cycling raises AICAR, leading to AMPK phosphorylation and metabolic switching (↑ glucose utilization, ↑ lipid catabolism).PMC

• Nuclear stress-response (ARE genes): Stress-induced nuclear MOTS-c co-opts ARE transcriptional programs (e.g., Nrf2-responsive genes) that augment antioxidant defenses and proteostasis.PMC

• Muscle anabolism/atrophy modulation: In muscle cells and mice, MOTS-c lowers myostatin and atrophy signaling, improving markers of muscle maintenance; precise upstream effectors are still being elaborated.PMC

• T-cell immunometabolism: In autoimmune diabetes models, MOTS-c reprograms T-cell phenotype and function, modulating inflammatory responses.PMC

CNS vs peripheral effects

• Peripheral predominance: Most data highlight skeletal muscle, liver, adipose, islets, bone, and immune cells as primary sites of action. The extent of blood–brain barrier penetration in vivo is Unknown.

• CNS-linked outcomes: Exercise performance and stress-response transcription could involve systemic–CNS crosstalk, but direct central pharmacology of MOTS-c in humans remains Not established.Nature

Hormonal, metabolic, immune interactions

• Metabolic homeostasis: Improves insulin sensitivity, promotes glucose uptake in muscle, and increases metabolic flexibility in rodents and cells.Cell

• Exercise adaptation: Endogenous levels rise with acute/chronic exercise and aging muscle shows context-specific changes (plasma down, muscle up).Nature+1

• Immune modulation: Alters T-cell profiles and reduces inflammatory signaling in disease models (autoimmune diabetes; radiation-induced lung injury).PMC+1

Evidence grading (A–C)

• A (replicated): AMPK-linked metabolic regulation (folate–purine–AICAR axis), nuclear translocation and stress-response gene activation, exercise induction, and improved metabolic phenotypes in rodents.Cell+2PMC+2

• B (translational/observational): Age- and exercise-associated changes in circulating/skeletal muscle MOTS-c in humans; disease-associated cross-sectional findings (e.g., dialysis, cancer cohorts) as biomarker signals.Aging-US+2PubMed+2

• C (uncertain): Defined human therapeutic effects, PK/PD, and long-term safety—Not established; the only in-human compound tested is an analogue (CB4211), not MOTS-c.GlobeNewswire

Pharmacokinetics & Stability

ADME profile (current knowledge)

• Absorption: Specific bioavailability by route for native MOTS-c in humans is Not established.

• Distribution: As a 16-mer peptide, MOTS-c likely distributes primarily to extracellular fluid and well-perfusedtissues; targeted data are sparse.

• Metabolism & excretion: Presumed proteolytic degradation with renal/hepatobiliary clearance of fragments, as with many small peptides; direct human metabolite mapping is Not established.

Notes: A 2024 mouse study tracked plasma kinetics after a single dose and showed relatively short plasma persistencewith tissue activity, but peer-reviewed human PK for native MOTS-c has not been published.ScienceDirect

Plasma half-life & degradation pathways

• Human t½: Unknown/Not established.

• Preclinical hints: Mouse plasma time-course experiments (7.5–15 mg·kg⁻¹) indicate rapid distribution/clearancewith measurable tissue responses; exact interspecies scaling is uncertain.PMC+1

Stability in vitro & in vivo

• In vitro: Stable under conventional experimental conditions over the timeframes used for metabolic assays; sequence is not cyclized, so peptidase susceptibility is expected.

• In vivo: Functional effects can outlast plasma residence, consistent with signal amplification (e.g., AMPKactivation, nuclear transcriptional changes). Quantified human stability data are lacking.

Storage/reconstitution considerations

Peer-reviewed literature does not provide standardized, product-agnostic shelf-life curves for research vials of MOTS-c. Typical peptide handling (cold chain, protect from light, minimize freeze–thaw) applies. Validated lot-specific stability is vendor/manufacturer-dependent.

Preclinical Evidence

Animal and in vitro studies—selected highlights

Metabolic regulation & insulin sensitivity

• Diet-induced obesity model (mouse): MOTS-c improved insulin sensitivity, increased glucose utilization (higher RER), and increased thermogenesis despite no change in spontaneous activity. Investigational dosing: 0.5 mg·kg⁻¹·day⁻¹ i.p. for 21 days.PMC

• Cell culture: MOTS-c enhanced glucose uptake via GLUT4 and activated AMPK; the upstream link involved AICAR accumulation from folate/purine pathway modulation.Cell+1

Exercise, proteostasis, and healthspan (mouse/human)

• Nature Communications 2021: MOTS-c improved physical performance in young, middle-aged, and old mice; intermittent late-life dosing (3×/week) increased physical capacity and healthspan indices. In humans, exerciseacutely increased muscle/blood MOTS-c; MOTS-c regulated nuclear genes in muscle and myoblast adaptation to stress. Investigational mouse regimens specified by study protocol (intermittent injections).Nature

• Training & aging: Human observational work shows plasma MOTS-c declines with age, yet skeletal muscleMOTS-c increases with long-term training; a single dose (15 mg·kg⁻¹) in mice improved running performance. Investigational dose: 15 mg·kg⁻¹ i.p. (mouse).Aging-US+1

Immune and islet biology

• Autoimmune diabetes (mouse): MOTS-c reprogrammed T-cells and improved disease features in NOD mice; circulating levels were lower in people with T1D than in controls (observational human cohort). Investigational dosing per study protocol (systemic).PMC

• Islet senescence (2025): MOTS-c reduced β-cell/islet senescence across models (aged mice, NOD mice, insulin antagonist model), with gene expression suggesting downregulation of mTOR-related programs. Investigational doses per study (systemic).Nature

Liver disease and NASH

• NASH-diet model (2024): MOTS-c alleviated steatosis, apoptosis, and inflammation, with both preventive and therapeutic effects reported in mice; mechanisms included protection of mitochondrial function and Bcl-2stabilization. Investigational dosing specified in study.ScienceDirect+1

Radiation-induced pneumonitis (RP) model

• Mouse RP (2024): Thoracic irradiation decreased endogenous lung MOTS-c; exogenous MOTS-c reduced RPand inhibited oxidative stress, inflammation, and apoptosis in epithelial models. Investigational dosing per protocol (systemic).MDPI

Muscle maintenance & atrophy

• Myostatin/atrophy signaling: MOTS-c reduced myostatin and atrophy markers in rodent/human cell models and improved muscle function; a MOTS-c analogue is in early clinical testing (see CB4211 below).PMC

Bone metabolism

• Bone remodeling review (2023): Evidence suggests action on osteoblast/osteoclast dynamics and bone metabolism; mechanistic and in vivo data are growing but still emergent.Frontiers

Dose ranges tested (illustrative; all investigational)

• Metabolic (HFD mice): 0.5 mg·kg⁻¹·day⁻¹ i.p. × 3 weeks improved insulin sensitivity and substrate use.PMC

• Performance (acute mice): 15 mg·kg⁻¹ improved running time/distance; long-term intermittent regimens (3×/week) enhanced healthspan indices in older mice.PMC+1

• Immune/islet models: Systemic regimens vary (e.g., daily or intermittent injections) depending on model (NOD, senescence, insulin antagonist); study-specific details apply.PMC+1

• Liver injury/NASH diet: Preventive and therapeutic schedules reported; typical preclinical systemic injections over weeks.ScienceDirect

Comparative efficacy/safety (preclinical)

• Efficacy: Consistent improvements across metabolic, exercise, immune, and organ-injury models.

• Safety: Animal studies generally report good short-term tolerability at test exposures. However, GLP-style, chronic toxicology packages for MOTS-c are not publicly available.

Limitations

• Species differences and diverse dosing regimens complicate translation.

• No definitive receptor has been identified (intracellular/nuclear mechanisms predominate).

• Human PK and long-term safety remain Not established.

Human Clinical Evidence

Summary: There are no completed, peer-reviewed Phase 2/3 trials of native MOTS-c. The most advanced clinical information concerns the analogue CB4211 in Phase 1a/1b, with company-reported topline data. Human observational/physiology studies evaluate MOTS-c as a biomarker or exercise-induced factor, not as an administered investigational drug.

Early-phase clinical analogue (CB4211)

• Design: Phase 1a/1b (healthy adults; overweight adults with obesity and elevated ALT/AST).

• Results (company-reported): Well-tolerated with no serious adverse events; in Phase 1b (4 weeks), ALT/ASTreductions (significant), glucose decreases, and a trend to lower body weight versus placebo. The most common AEs were mild-to-moderate injection-site reactions. (Exploratory pharmacodynamics; peer-reviewed publication not cited in 2021 press statements.)GlobeNewswire

• Relevance: CB4211 is not MOTS-c, but suggests that MOTS-c-like pharmacology may be tolerated short-term in humans. Still, therapeutic safety and efficacy of native MOTS-c remain Not established.

Observational/physiology in humans

• Aging: Plasma MOTS-c declines with age, whereas skeletal muscle MOTS-c increases with long-term training; patterns may reflect compartment-specific regulation.Aging-US

• Exercise: Acute exercise upregulates MOTS-c in skeletal muscle and blood, supporting a role as an exercise-induced mitokine.Nature

• Chronic disease cohorts: Circulating MOTS-c has been explored as a biomarker (e.g., hemodialysis cardiovascular risk; oncology contexts), but interventional data are lacking.PubMed+1

Safety signals/adverse events (public-health perspective)

• Regulatory/anti-doping advisories: Agencies (e.g., USADA) note that MOTS-c is not approved for human use; reports from self-experimentation forums include palpitations, insomnia, fever, and injection-site reactions. These are anecdotal and uncontrolled; safety in humans remains Unknown.U.S. Anti-Doping Agency (USADA)

ClinicalTrials.gov IDs

• Specific native MOTS-c interventional IDs with published results are not available as of this writing; reviews mention ongoing early-stage efforts, but completed, peer-reviewed outcomes are lacking.eDMJ

Comparative Context

Related peptides/approaches

• Other MDPs: Humanin, SHLPs—share mitochondrial origin but differ in targets and phenotypes.

• AMPK activators: AICAR, metformin—MOTS-c intersects the AMPK axis via AICAR, offering a peptide-based route to metabolic reprogramming (mechanistically overlapping but not identical).Alzheimer's Drug Discovery Foundation

Advantages (research perspective)

• Endogenous origin with stress-responsive regulation (exercise, metabolic stress).

• Dual action: cytoplasmic metabolic and nuclear transcriptional programs.

• Broad preclinical efficacy across metabolic, exercise, and injury models.

Disadvantages / constraints

• Human PK/PD, receptor identity, and long-term safety are Not established.

• Dose-exposure relationships and bioavailability by clinically practical routes remain undefined.

• Reliance on analogue data (CB4211) for human safety signals.

Research category placement

MOTS-c is a mitochondrial stress-response peptide and exercise-induced mitokine, suitable as a mechanistic tool to interrogate AMPK activation, retrograde mitonuclear signaling, exercise adaptation, and stress resilience in cells and model organisms.

Research Highlights

• Metabolic switch via AMPK: MOTS-c reroutes one-carbon/purine metabolism to AICAR, activating AMPKand improving insulin sensitivity and substrate use in mice. Investigational mouse dose: 0.5 mg·kg⁻¹·day⁻¹.Cell+1

• Nuclear programing under stress: Nuclear translocation allows MOTS-c to engage ARE-driven transcription and stress-response genes.PMC

• Exercise-induced mitokine: Human exercise elevates MOTS-c; in mice, intermittent dosing across lifespan improves performance and healthspan metrics.Nature

• Disease-model breadth: Signals in autoimmune diabetes (T-cell reprogramming), NASH-diet liver injury, radiation pneumonitis, muscle atrophy, and bone metabolism highlight pleiotropy.Frontiers+4PMC+4ScienceDirect+4

• Clinical analogue: CB4211 Phase 1a/1b showed tolerability and biomarker improvements over 4 weeks (press-release level).GlobeNewswire

Conflicting/uncertain areas

• Human dosing/PK and BBB penetration: Unknown.

• Receptor-level mediation: No definitive cell-surface receptor; intracellular/nuclear mechanisms dominate current models.

• Long-term human safety/efficacy: Not established.

Potential Research Applications (no clinical claims; research-use framing)

1. Metabolic rewiring & AMPK biology
   Use MOTS-c to probe folate–purine flux, AICAR dynamics, and AMPK activation in primary myotubes and hepatocytes; integrate stable-isotope tracing and phosphoproteomics to map upstream flux and downstream metabolic switches.Cell

2. Mitonuclear stress signaling
   Model nuclear translocation kinetics under glucose restriction, oxidative stress, or exercise mimetics; ChIP-seq/ATAC-seq to resolve ARE-associated gene regulation by MOTS-c and co-factors (e.g., Nrf2).PMC

3. Exercise physiology & aging
   In mice, evaluate intermittent vs continuous MOTS-c dosing on VO₂max, running endurance, proteostasis, and frailty indices; in human explants or organoids, test contraction-mimetic paradigms and myokine cross-talk.Nature

4. Islet senescence & immunometabolism
   Dissect how MOTS-c remodels β-cell senescence networks and T-cell function (single-cell RNA-seq; cytokine milieus) across autoimmune and metabolic stress models.Nature+1

5. Organ protection
   Test pre-/post-injury MOTS-c regimens in NASH, cardiac/lung irradiation, or ischemia–reperfusion models, read out mitochondrial respiration, Bcl-2 stability, and oxidative stress markers.ScienceDirect+1

6. Analogue development & PK
   Derive stability-enhanced or target-directed analogues; perform head-to-head PK/PD and tissue distribution in rodents/large animals to enable rational clinical translation (learning from CB4211).GlobeNewswire

Safety & Toxicology

Preclinical toxicity data

Across rodent studies, MOTS-c has been generally well tolerated at investigational exposures in the short term; formal GLP repeat-dose, genotoxicity, reproductive, and carcinogenicity packages are Not established in the public domain.

Known/theoretical molecular risks

• Pathway overlap with AMPK activators: Potential interactions with other AMPK-targeted agents (e.g., metformin) are theoretical and require careful study.Alzheimer's Drug Discovery Foundation

• Immunomodulation: While anti-inflammatory/immune-reprogramming effects are reported, long-term consequences for host defense are Unknown.

• On-target metabolic shifts: Chronic AMPK activation can influence autophagy, lipid handling, and mitochondrial biogenesis; tissue-specific risks are unclear.

Human safety observations

• Native MOTS-c: No completed, peer-reviewed clinical trials; safety in humans is Unknown.

• Public-health statements: Anti-doping/regulatory bodies caution that unapproved MOTS-c products have unknown purity and uncharacterized risk profiles; anecdotal reports include palpitations, insomnia, fever, and injection-site irritation.U.S. Anti-Doping Agency (USADA)

• Analogue (CB4211): Well tolerated over 4 weeks in Phase 1b with injection-site reactions most common; these data do not establish safety for MOTS-c itself.GlobeNewswire

Data gaps

• Human PK/PD, dose–response, DDIs, immunogenicity, and chronic safety need rigorous evaluation.

• Target engagement biomarkers (e.g., AICAR, p-AMPK, ARE transcriptional readouts) for humans are not validated.

Limitations & Controversies

• Translational gap: Strong preclinical and physiology evidence contrasts with a lack of completed human efficacy trials of native MOTS-c.

• Mechanistic uncertainties: No definitive cell-surface receptor; intracellular entry routes and nuclear partnersremain under active investigation.BioMed Central

• Heterogeneity in observational cohorts: Age, exercise status, sex, and mtDNA haplogroups may influence circulating MOTS-c responses, complicating biomarker generalization.Nature

• Commercial landscape: “Research-use only” products exist online; regulatory authorities warn against non-approved use.U.S. Anti-Doping Agency (USADA)

Future Directions

1. Human first-principles studies
   Conduct Phase 1 trials of native MOTS-c with graded SC/IV dosing to define PK/PD, tolerability, and target engagement (e.g., p-AMPK, AICAR surrogates) under metabolic clamp/exercise conditions.

2. Precision physiology
   Stratify volunteers by mtDNA haplogroup, age, and training status to assess differential MOTS-c dynamics and responses (guided by ethnic/mtDNA variation observations).Nature

3. Mechanism mapping
   Apply proteomics/chemical biology to identify potential binding partners, import pathways, and nuclear cofactors; dissect ARE co-regulation with Nrf2 during stress.

4. Comparative analogues
   Advance stability-enhanced or tissue-targeted analogues with rigorous exposure–response modeling; compare to AMPK activators for efficacy and safety windows (learning from CB4211).GlobeNewswire

5. Disease-specific trials
   If justified by Phase 1, pilot randomized studies in insulin-resistant or NAFLD/NASH populations using validated imaging/biomarker endpoints; extend to older adults with functional (exercise) outcomes.

6. Biomarker development
   Standardize MOTS-c assays (plasma vs tissue), validate exercise-induced dynamics, and define clinical cut-points for risk stratification (e.g., dialysis, cardio-metabolic cohorts).PubMed

References

1. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. (Folate–purine–AICAR–AMPK axis; metabolic benefits; dosing in HFD mice.) Cell

2. Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression. Cell Metab. 2018;28(3):516–524.e7. (Nuclear translocation; ARE-linked transcription.) PMC

3. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded peptide that enhances physical performance and increases healthspan in mice. Nat Commun. 2021;12:4703. (Exercise induction; performance/healthspan benefits.) Nature

4. Wan W, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms. J Transl Med. 2023. (Mechanistic review: folate–purine–AICAR–AMPK; stress responses.) PMC

5. Zheng Y, et al. MOTS-c: a promising mitochondrial-derived peptide for human disease treatment. Front Endocrinol. 2023. (Disease-oriented review; anti-inflammatory, insulin-sensitizing effects.) PMC

6. Hyatt JPK, et al. MOTS-c increases in skeletal muscle following long-term training and acutely improves running performance in mice. Physiol Rep. 2022. (Training and acute dose performance effects.) PMC

7. Cuyàs E, et al. Circulating MOTS-c in breast cancer patients (metformin trial context). Aging (Albany NY). 2022. (Biomarker study, paired sera.) PMC

8. Bolignano D, et al. Circulating MOTS-c may refine mortality/CV risk prediction in hemodialysis. J Nephrol. 2024. (HD cohort biomarker signal.) PubMed

9. Kong BS, et al. Mitochondrial-encoded peptide MOTS-c, diabetes, and aging. Diabetes Metab J. 2023. (Clinical perspective; trials in progress.) eDMJ

10. Kong BS, et al. Mitochondrial-encoded peptide prevents pancreatic islet T-cell dysfunction (autoimmune diabetes models). Signal Transduct Target Ther. 2021. (Immunometabolism.) PMC

11. Lu H, et al. MOTS-c alleviates NASH-diet liver injury and improves mitochondrial function. Cell Reports. 2024. (Preventive/therapeutic effects; Bcl-2 stability.) Cell

12. Zhang Y, et al. MOTS-c alleviates radiation-induced pneumonitis in mice. Antioxidants. 2024;13(5):613. (Lung injury model; oxidative stress/inflammation/apoptosis.) MDPI

13. Kumagai H, et al. MOTS-c reduces myostatin and muscle atrophy signaling. iScience. 2021. (Muscle maintenance; analogue mention in clinical testing.) PMC

14. Yi X, et al. Role of MOTS-c in bone metabolism. Front Physiol. 2023. (Bone remodeling overview.) Frontiers

15. Aging (Albany NY) study: Circulating MOTS-c declines with age; skeletal muscle expression increases with training. 2020. Aging-US

16. USADA: What is the MOTS-c peptide? 2024. (Regulatory/anti-doping advisory; safety Unknown.) U.S. Anti-Doping Agency (USADA)

17. CohBar press release: CB4211 Phase 1a/1b topline results (NASH/obesity). 2021. (Analogue tolerability; exploratory biomarker changes.) GlobeNewswire

Investigational doses in key preclinical studies:
• 0.5 mg·kg⁻¹·day⁻¹ (i.p.) × 21 days in HFD mice improved glucose utilization and thermogenesis (investigational dose used in study Lee 2015). PMC
• 15 mg·kg⁻¹ (i.p.) single dose in untrained mice improved endurance (investigational dose used in Physiolog Rep. 2022). PMC
• Intermittent dosing (3×/week) in late-life mice increased physical capacity/healthspan (investigational regimen used in Nat Commun. 2021). Nature

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.