How does it work?
Studies have investigated how MOTS-c appears to affect a central "energy sensor" system in cells called AMPK. When AMPK is activated, cells shift towards using sugar and fat as fuel. In experiments, MOTS-c has been linked to increased glucose uptake in muscle, including via the transporter GLUT4. Another property researchers have explored is that under stress the peptide can move into the cell nucleus and influence which genes are switched on and off. This is largely based on cell and animal models.
Technical mechanism
16-amino-acid peptide encoded in mitochondrial DNA. Translocates to the cell nucleus and activates AMPK signalling pathways for glucose uptake and fatty acid oxidation.
What is being researched?
- Insulin sensitivity and how the body regulates blood sugar (animal and cell studies)
- Activation of AMPK – the cells' energy sensor – and general energy metabolism
- Muscle function, physical capacity and age-related decline (animal studies)
- Body weight, fat tissue and high-fat-diet-induced obesity in animal models
- Cardiovascular function (animal models and observational data in humans)
- Bone health and osteoporosis-like bone loss (animal and cell studies)
About the evidence: Almost all knowledge about MOTS-c comes from experiments in cells and animals (especially mice and rats). Human data are so far few and early – most are small observational studies that measure the body's natural MOTS-c levels, not large treatment studies. None of this is an approved treatment, and the content here is intended as research information only (Research Use Only).
Research profile
Studies and sources
The links go to independent research databases (PubMed, PubMed Central, ClinicalTrials.gov). The studies are in English and open in a new tab.
Metabolism, insulin sensitivity and AMPK signalling
The early basic research on MOTS-c is about energy metabolism. Studies in mice and cells have explored how the peptide affects insulin sensitivity and activates the energy sensor AMPK.
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance PreclinicalPubMed· 2015
In this study, the researchers describe a small peptide called MOTS-c that is produced from the cells' mitochondria (power plants). In experiments with mice, MOTS-c treatment prevented insulin resistance linked to age and a high-fat diet, and also counteracted obesity from high-fat food. The peptide appears to act primarily in skeletal muscle. This is an animal and laboratory study, and the findings apply to mice, not humans.
- MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism ReviewPubMed· 2016
This review describes MOTS-c, a small peptide produced from the mitochondria's own genetic material. The authors explain that MOTS-c acts on skeletal muscle and improves sugar metabolism, and that it may be relevant to obesity, diabetes, exercise and ageing. The article presents MOTS-c as an entirely new type of signal from the mitochondria that helps regulate metabolism within and between cells.
- MOTS-c: an equal opportunity insulin sensitizer ReviewPubMed· 2019
Based on the title: This review discusses MOTS-c as a peptide that appears to improve insulin sensitivity in different groups.
- Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging ReviewPubMed· 2023
This review describes MOTS-c, a peptide produced from the mitochondria's 12S rRNA gene. The authors explain that more MOTS-c is produced during stress or exercise and that it can move into the cell nucleus to switch on genes that protect against stress. The peptide acts mainly via an energy signalling pathway (AMPK) and affects energy metabolism, insulin resistance, inflammation, exercise and ageing. The article summarises research on how MOTS-c may contribute to healthy ageing.
Exercise, muscle and ageing
MOTS-c levels appear to rise with physical activity, and several animal studies have investigated whether the peptide can affect muscle function and physical capacity across the lifespan.
- MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis PreclinicalPubMed· 2021
In this study, the researchers found that MOTS-c, a peptide from the mitochondria, improved physical performance in mice of all ages – young, middle-aged and old. Treatment started late in life increased both physical capacity and healthy lifespan in the mice. In humans, they saw that exercise increases the body's own production of MOTS-c in muscle and blood. The treatment experiments themselves were done in mice, while the human part is only an observation linked to exercise.
- MOTS-c modulates skeletal muscle function by directly binding and activating CK2 PreclinicalPubMed· 2024
In this laboratory and animal study, the researchers show that MOTS-c acts by binding to and activating an enzyme called CK2. In mice, MOTS-c counteracted muscle wasting and increased the muscle's uptake of sugar, but the effect disappeared when CK2 was inhibited. A natural gene variant (K14Q) bound less well to CK2. Men with this variant had a higher risk of muscle loss and type 2 diabetes, while women had a lower risk at certain ages. The treatment experiments were done in mice and cells.
- Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration PreclinicalPubMed· 2024
In this animal study, the researchers investigated whether the peptide MOTS-c can counteract muscle wasting when mice's legs were immobilised in a cast. Without treatment the mice lost around 15 per cent of muscle mass, while MOTS-c treatment limited the loss to about 5 per cent. The treatment also dampened inflammation in the body and reduced fat accumulation in the muscle. The findings suggest that MOTS-c may protect against muscle wasting in this mouse model.
Cardiovascular health
Researchers have explored the relationship between MOTS-c and the cardiovascular system, both in animal models and by measuring the body's natural levels in patient groups.
- MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats PreclinicalPubMed· 2023
In this animal study of diabetic rats, the researchers investigated the effect of MOTS-c on the heart. Eight weeks of treatment repaired damage to the heart's mitochondria and preserved the heart's pumping and filling function. Analyses suggested that MOTS-c acted partly by dampening cell death in the heart muscle via specific genes and signalling pathways. The findings point to possible treatment targets in diabetes and heart disease in rats, but have not been investigated in humans here.
- The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study Clinical (human)PubMed· 2024
In this study of 94 dialysis patients, the researchers investigated whether the level of the peptide MOTS-c in the blood can help predict death and cardiovascular events. MOTS-c levels were higher in dialysis patients than in healthy people, and higher still in those who later had such events. When MOTS-c was added to standard risk factors, the prognostic models improved somewhat. The authors believe MOTS-c may provide additional information about risk, but that larger studies are needed.
Bone and skeletal health
A number of animal and cell studies have looked at whether MOTS-c can affect bone cells and bone loss, including in models of osteoporosis.
- Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation PreclinicalPubMed· 2016
In this animal study, mice that had had their ovaries removed received MOTS-c injections for 12 weeks to see whether the peptide could protect against osteoporosis. MOTS-c clearly reduced bone loss, measured by CT scanning. The researchers found that MOTS-c inhibited the formation of cells that break down bone, and that the effect occurred via activation of the energy signalling pathway AMPK. The findings suggest that MOTS-c may counteract osteoporosis in this mouse model.
- MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway PreclinicalPubMed· 2018
In this laboratory experiment with bone marrow cells from rats, the researchers investigated whether MOTS-c can counteract osteoporosis. MOTS-c caused the cells to develop into bone-building cells and formed more calcified nodules. The effect occurred via a specific signalling pathway (TGF-β/Smad), and disappeared when a key gene in this pathway was knocked out. The findings suggest that MOTS-c may promote bone formation in cell experiments, but this has not been investigated in humans here.
Human data
Human research is still at an early stage and consists of smaller observational studies that measure the body's natural MOTS-c levels in different patient groups.
- Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects Clinical (human)PubMed· 2019
In this study of women with polycystic ovary syndrome (PCOS) and healthy controls, the researchers investigated how the peptide MOTS-c in the blood responds to fat and insulin. Administration of fat clearly increased MOTS-c levels in both groups, while insulin dampened this increase. Eight weeks of moderate exercise did not change MOTS-c levels. According to the authors, this is the first study to show that fat increases MOTS-c in humans, while insulin dampens the response.