MOTS-c
Also known as Mitochondrial ORF of the 12S rRNA type-c, Mitochondrial-derived peptide MOTS-c, CB4211 (analog)
MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA that acts as a metabolic signal, improving insulin sensitivity and exercise capacity in mice. People use it for fat loss, endurance, and metabolic aging.
Overview
MOTS-c was identified in 2015 by Changhan Lee and Pinchas Cohen at the University of Southern California. It is encoded in a short open reading frame inside the mitochondrial 12S ribosomal RNA gene, which was assumed for decades to make only RNA. That makes it one of a small family of mitochondrial-derived peptides, alongside humanin and the SHLPs, and it reframed mitochondria as organelles that send out their own hormone-like signals.
The mouse data are what drive interest. MOTS-c injections prevented diet-induced obesity and insulin resistance, improved glucose handling in aged mice, and, in a 2021 study, restored exercise capacity in old mice to the point where treated animals doubled their running time. Levels in muscle and blood rise with exercise in humans and decline with age. A natural variant of the MOTS-c sequence found in East Asian populations is linked to higher type 2 diabetes risk, which is indirect human evidence that the peptide matters metabolically.
Direct human treatment data are limited. CohBar developed a modified analog, CB4211, which completed a phase 1a/1b study in people with obesity and fatty liver, showing acceptable safety and modest changes in glucose and body weight, before the company changed direction. Native MOTS-c has not been through a proper human trial. The community treats it as an exercise mimetic and metabolic aid, usually injected a few times per week.
How it works
MOTS-c works largely through the folate and methionine cycles. It inhibits an enzyme in the folate cycle, which lowers purine synthesis and raises AICAR, an endogenous activator of AMPK. AMPK activation increases glucose uptake in skeletal muscle, boosts fatty acid oxidation, and improves mitochondrial biogenesis, which together resemble the effects of exercise. Under metabolic stress MOTS-c also moves from the cytoplasm into the nucleus, where it binds stress-response transcription factors including NRF2 and adjusts expression of antioxidant and metabolic genes. It acts on muscle preferentially, with smaller effects on liver and fat. Its rise with exercise and decline with age suggest it is a normal part of how mitochondria communicate their energy status to the rest of the body.
What the research shows
- rodentMOTS-c prevented high-fat-diet obesity and insulin resistance in mice and improved insulin sensitivity in aged mice.
- rodentMOTS-c treatment roughly doubled running capacity in old mice and improved physical performance in young mice on a high-fat diet.
- in vitroMOTS-c translocates to the nucleus during metabolic stress and regulates stress-response gene expression.
- human pilotExercise raised MOTS-c levels in human skeletal muscle and plasma.
- human pilotThe CB4211 analog completed a phase 1 study in obesity and fatty liver with acceptable safety and modest metabolic signals.
- human pilotA natural MOTS-c sequence variant in East Asian populations is associated with increased type 2 diabetes risk.
Evidence labels: rodent and in vitro mean no human data for that finding. Human pilot means small, often uncontrolled. Human RCT means randomized and controlled. Clinical means an approved drug with regulatory data.
Dose calculator
U-100 insulin syringeUnits are a volume on the syringe, not an amount of peptide. Concentration changes every time you change the water volume. The standalone calculator explains the math.
Dosing and protocol
Community protocols range widely. Mouse studies used 5 to 15 mg per kg, which scales to much larger human doses than anyone uses, so the human-equivalent dose is unknown.
4-8 weeks, then reassess
Morning or before exercise. Some people dose fasted.
| Vial | Suggested water | Concentration | Low dose draw |
|---|---|---|---|
| 10 mg | 1 mL | 10 mg/mL | 50 units |
| 20 mg | 2 mL | 10 mg/mL | 50 units |
| 40 mg | 4 mL | 10 mg/mL | 50 units |
Lyophilized: fridge or freezer, away from light. Reconstituted: fridge 2-8C, use within 4 weeks.
Cautions
- ▲No human trial of native MOTS-c exists; only the analog CB4211 has phase 1 data.
- ▲Injection site reactions and transient fatigue or flushing are the most common reports.
- ▲Some people note temporary drops in blood glucose; people on glucose-lowering drugs should watch for that.
- ▲Mouse effective doses per kilogram are far above community doses, so the human-effective range is a guess.
- ▲Marketed as an exercise pill; it is not a substitute for actually training.
Commonly stacked with
SS-31 protects mitochondrial membranes while MOTS-c drives metabolic signaling, so people pair them for a mitochondrial stack.
Some people add MOTS-c during GLP-1 fat loss hoping to preserve muscle and exercise capacity, though there is no combined data.
NAD+ supports the same mitochondrial energy pathways that MOTS-c signals through.
Frequently asked
Is MOTS-c an exercise mimetic?
In mice, treatment reproduced several effects of exercise, including AMPK activation in muscle and improved endurance. Levels also rise naturally with exercise in humans. Whether an injected dose gives a person any meaningful fraction of what training does has not been tested.
Will it help me lose weight?
It prevented fat gain in mice on a high-fat diet and the CB4211 analog produced modest weight changes in a small phase 1 study. That is a long way from a fat loss drug. Expect small effects at most, and only alongside diet and exercise.
How is it different from humanin?
Both are mitochondrial-derived peptides, but humanin comes from the 16S rRNA gene and leans toward neuroprotection and cell survival, while MOTS-c comes from the 12S rRNA gene and is mainly a metabolic regulator acting on muscle.
How often do people inject it?
Two or three times per week at 5 to 10 mg is the most commonly cited protocol. Some use it daily at lower doses or only around training sessions. None of these schedules have human data behind them.
References
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 2015
- MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 2021
- The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism, 2018
- A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide MOTS-c. Aging, 2021