MOTS-c

Also known as: Mitochondrial open reading frame of the 12S rRNA type-c, Mitochondrial-derived peptide (MDP)

Evidence: Preclinical

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Overview

Sixteen-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA gene; shown in animal models to activate AMPK and act as an exercise mimetic improving insulin sensitivity.

MOTS-c is a 16-amino-acid microprotein encoded in a short open reading frame inside the mitochondrial 12S rRNA gene. It was described in 2015: treatment prevented age-dependent and high-fat-diet insulin resistance and diet-induced obesity in mice, with skeletal muscle as the apparent target organ and inhibition of the folate cycle and de novo purine synthesis leading to AMPK activation (Lee 2015). Injected MOTS-c improved physical performance in young, middle-aged and old mice and, started at 23.5 months, raised physical capacity late in life (Reynolds 2021). It also limited immobilisation-induced muscle atrophy in mice (Kumagai 2024). In humans only endogenous changes are documented: exercise raises MOTS-c in muscle and circulation (Reynolds 2021). A phase 2a trial in prediabetes began recruiting in 2026.

Benefits

Insulin sensitivity and reduced diet-induced obesity (mouse), physical capacity in young to old mice, protection against immobilisation muscle atrophy (mouse); exercise raises endogenous levels (human)

Dosing reference

Research dose: 5-10 mg per injection (research-community range; rodent studies used 5-15 mg/kg/day intraperitoneally, which does not convert to a fixed human dose)
Range: 5000 to 10000 mcg, 1-3x weekly
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg

Community protocols use subcutaneous injection. Published dosing is rodent and intraperitoneal: 5 mg/kg three times weekly from 23.5 months of age for the healthspan work (Reynolds 2021) and 15 mg/kg/day for 8 days in the immobilisation model (Kumagai 2024). The recruiting phase 2a trial uses a fixed once-daily subcutaneous dose for 12 weeks (NCT07505745). No human pharmacokinetic data.

Mechanism

MOTS-c is encoded within the mitochondrial 12S rRNA gene and acts as a mitochondrial-derived signalling peptide. In the original report its cellular action was inhibition of the folate cycle and the de novo purine synthesis it feeds, which raises AICAR levels and activates AMPK, with skeletal muscle as the primary target organ (Lee 2015). It binds and activates casein kinase 2 in muscle (Kumagai 2024, iScience). Rodent work links treatment to PGC-1alpha expression, AMPK signalling and improved mitochondrial respiration (Yang 2021; Gudiksen 2026). Endogenous expression rises with exercise in mouse and human muscle and falls with age (Reynolds 2021). Nuclear translocation under metabolic stress is reported in cell work (Lee 2015).

Evidence

Preclinical: animal or in vitro data only

Treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity in mice; target organ skeletal muscle (Lee et al., 2015)
Improved physical performance in young, middle-aged and old mice; intermittent treatment from 23.5 months raised physical capacity and healthspan (Reynolds et al., 2021)
15 mg/kg/day for 8 days limited immobilisation-induced muscle loss in mice to 5% versus 15% in controls, with less muscle lipid infiltration (Kumagai et al., 2024)
Exercise raised endogenous MOTS-c in human skeletal muscle and circulation; levels decline with age (Reynolds et al., 2021)
Aerobic and resistance exercise changed circulating MOTS-c in breast cancer survivors (Dieli-Conwright et al., 2021); circulating mitochondrial-derived peptide levels track metabolic state in a meta-analysis (Zhou et al., 2024)
Human-trial status: no completed trial of MOTS-c itself. The analog CB4211 completed a phase 1a/1b safety and PK study (n=88, subcutaneous, CohBar, NCT03998514) and a phase 2a of MOTS-c in prediabetes with overweight or obesity began recruiting in 2026 (n=120 estimated, NCT07505745)

References

Side effects

No published adverse-event data for MOTS-c in humans; the recruiting phase 2a trial is the first to collect it (NCT07505745). The analog CB4211 completed a phase 1a/1b safety study in 88 subjects, with results not published in the peer-reviewed literature (NCT03998514). Injection-site irritation and transient fatigue are commonly reported (anecdotal). Effects of repeated dosing of a mitochondrial-derived peptide in humans are uncharacterised.

Storage

Storage: Refrigerate 2-8°C (36-46°F); general lyophilised-peptide guidance, no compound-specific CoA located
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not established; no pharmacokinetic study of MOTS-c in any species located. Rodent work dosed intraperitoneally once daily or 3x weekly (Lee 2015; Reynolds 2021)
Bioavailability: No bioavailability figure published. Rodent studies dosed intraperitoneally; the analog CB4211 was given subcutaneously in a phase 1a/1b trial (NCT03998514). Exercise raises endogenous MOTS-c in human muscle and plasma (Reynolds 2021)
Molecular weight: 2174.64 Da
Sequence: MRWQEMGYIFYPRKLR