MOTS-c
also known as mitochondrial open reading frame of the 12S rRNA-c, MOTSc
16-amino-acid mitochondrial-encoded peptide (mitokine) translated from the 12S rRNA short open reading frame. Activates AMPK via folate-cycle inhibition, increasing fatty acid oxidation, glucose tolerance, and mitochondrial biogenesis. Endogenous levels decline with age and rise with exercise — frequently described as an exercise-mimetic. No completed human RCT to date; first MOTS-c-analog Phase 1a/1b (CB4211) completed 2021.
At a glance
SQ · Variable · 2–3×/week
Mechanism
Primary target — Mitochondrial 12S rRNA sORF → folate-AICAR-AMPK axis [lee-2015].
Pathway — Folate cycle inhibition → ↑AICAR → AMPK phosphorylation → PGC-1α upregulation [lee-2015][kim-2018].
Downstream effect — Enhanced fatty acid oxidation, GLUT4-mediated glucose uptake, mitochondrial bioenergetics, anti-inflammation [lee-2015].
Origin — Endogenous 16-AA mitokine; mtDNA-encoded; declines with age; upregulated by exercise [reynolds-2021].
Feedback intact — Stress-responsive, AMPK-dependent nuclear translocation [kim-2018].
Dosage
Protocols described in the cited literature; not medical advice.
| Parameter | Value |
|---|---|
| Standard dose | 5–10 mg / week [lee-2015]Experimental, extrapolated from animal data. No human RCT-derived dose. |
| Frequency | 2–3× per weekShort half-life may necessitate more frequent dosing for saturation. |
| Lower / starter dose | 2.5–5 mg / weekRecommended due to limited human data. |
| Evidence basis | Animal + anecdotal [lee-2015][reynolds-2021][cb4211-phase1-2021]Phase 1a/1b CB4211 analog trial completed 2021; no native MOTS-c RCT published. |
| Duration | 4–12 weeks (experimental)Optimal cycle length unknown. |
| Reconstitution | Bacteriostatic water, 1–2 mL10 mg/mL at 1 mL. |
| Timing | Pre-workout or fasted state preferredActivity-context amplifies AMPK response. |
| Half-life | Minutes to hours (estimated)Systemically unstable; native MOTS-c PK in humans not fully characterised. |
Reconstitution
A pure mass-to-volume utility. Enter what you have in the vial; the atlas computes the volume per dose. No prescription information.
Evidence
Strong animal data · Mechanistic human studies · No completed human RCT
| Outcome | Finding |
|---|---|
| Primary fat target | Diet-induced / metabolic obesity; systemic fat utilization |
| Quantified reduction | Significant HFD fat gain ↓ [lee-2015]Murine models, dose-dependent (5 & 15 mg/kg). |
| IGF-1 impact | No direct IGF-1 pathway; AMPK-mediated |
| Effect on lean mass | High dose significantly ↑ lean mass in mice |
| Insulin sensitivity | Reversed HFD insulin resistance in 7 days (mice) [lee-2015] |
| Triglycerides | AMPK-driven FA oxidation suggests TG benefit (not directly measured) |
| Glucose metabolism | Improved glucose tolerance; GLUT4 upregulation [lee-2015] |
| Effect reversibility | Unknown — no long-term follow-up data |
| Context dependency | No effect in normal-chow mice; requires metabolic stress [reynolds-2021] |
| Key publication | Lee Cell Metab 2015 · Reynolds Nat Commun 2021 · Kim Cell Metab 2018 [lee-2015][reynolds-2021][kim-2018] |
Adverse events
Severities follow the FDA / CTCAE convention.
- — Pregnancy / breastfeeding (insufficient data)
- — Active cancer or cancer predisposition
- — AMPK pathway deficiency (efficacy nullified)
- — Use with cancer-promoting medications (theoretical)
Administration
- 01Reconstitution
Add 1–2 mL bacteriostatic water. At 10 mg/vial, 1 mL gives 10 mg/mL concentration. Roll gently to dissolve.
- 02Injection site
Subcutaneous — abdomen, thigh, or deltoid. Rotate sites to avoid lipohypertrophy. Pinch fat layer.
- 03Timing
Pre-workout or fasted state preferred — metabolic context amplifies AMPK response. 2–3× per week.
- 04Storage
Lyophilised: room temp, protected from light. Reconstituted: refrigerate, use within 21–30 days. Short systemic stability.
- 05Needle
27–31G insulin syringe. Short needle (4–6 mm) for SQ delivery. Clean technique mandatory.
Synergies
Sources
of 68 rendered claims carry a resolvable citation.
- [cb4211-phase1-2021]A first-in-human phase 1 study 2021 — A first-in-human phase 1 study of CB4211 (a MOTS-c analog) in obese subjects with type 2 diabetes
clinical-trial, 2021 - [kim-2018]Kim 2018 — The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress
Cell Metab, 2018 - [lee-2015]Lee 2015 — The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Cell Metab, 2015 - [reynolds-2021]Reynolds 2021 — MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Nat Commun, 2021