Everyone knows exercise is good for you. Far fewer people know what actually happens inside the body's cells when you work out. One answer came in 2015 from the University of Southern California. Researchers there discovered a small molecule that the body makes on its own and produces in larger amounts during exercise. They named it MOTS-c.
Since then, a number of studies have been published about it. They show that MOTS-c influences how the body handles sugar and fat, how muscles behave and how quickly physical fitness declines with age.
What Is MOTS-c?
MOTS-c is a peptide, a short chain of amino acids. It has only 16 of them, so it is much smaller than a typical protein. In the body, peptides often act as signals: one cell uses them to let others know what is happening and how to respond.
What makes MOTS-c unusual is where it comes from. The instructions for making it are not stored in the cell nucleus, where most of our DNA lives, but in the mitochondria. These are tiny structures inside cells that turn nutrients into energy. They have their own small set of DNA, which we inherit from our mothers.
For a long time, scientists believed mitochondrial DNA contained only a few dozen genes needed for energy production. Over time, however, it turned out that it also holds instructions for small signaling peptides. Researchers call them mitochondrial-derived peptides. The first one, humanin, was discovered in 2001. MOTS-c followed fourteen years later.
The name MOTS-c is an English abbreviation that describes where in the mitochondrial DNA the instructions for the peptide are found (in the gene for the so-called 12S ribosomal RNA). To understand what it does, though, the name itself doesn't matter much.
Mitochondria Can Send Messages
At school, we learned that mitochondria are the “powerhouses of the cell.” They make energy, and that's the end of their job. MOTS-c showed that this is only part of the story.
In 2018, a study in the journal Cell Metabolism found that when a cell is under pressure (for example, when it runs short of nutrients), MOTS-c moves out of the mitochondria and straight into the cell nucleus. There, it switches on genes that help the cell cope with stress, including genes that protect against oxidative damage.
It works a bit like the low-fuel warning light in a car. The light doesn't fix anything by itself, but it tells the driver that fuel is running low and it's time to drive more economically. MOTS-c plays the role of that warning light, and the cell nucleus plays the driver: it responds to the signal and changes how the cell manages its energy. This was an important discovery, because it showed that mitochondria are not just passive energy suppliers but actively influence how the whole cell behaves.
How MOTS-c Works
Most of MOTS-c's effects run through a single enzyme called AMPK, which acts as the cell's energy watchdog. When it detects that energy is running low, it triggers steps that help the cell top up or save energy:
- the cell starts taking in more sugar from the blood,
- it burns more fat,
- over time, it builds new mitochondria so it can produce more energy.
Incidentally, the same enzyme is also activated during exercise and fasting. That's one reason MOTS-c is so often mentioned in connection with physical activity.
Scientists have described exactly how MOTS-c switches AMPK on. It interferes with the metabolism of folic acid (folate), which causes a substance called AICAR to build up in the cell. AICAR, in turn, activates AMPK. In scientific terms, this is known as the folate–AICAR–AMPK pathway. The details aren't essential. What matters is the result: the cell starts using energy more economically and efficiently.
The 2015 Discovery: Mice That Didn't Gain Weight
The study in which MOTS-c was first described was published in 2015 in Cell Metabolism. It was led by Changhan Lee from the laboratory of Professor Pinchas Cohen.
The researchers found that MOTS-c acts mainly in the muscles. That makes sense, because muscles are among the tissues that use the most sugar in the body.
The experiment that attracted the most attention involved mice on a high-fat diet. One group also received MOTS-c, the other did not. The mice given MOTS-c gained less weight, and their bodies responded better to insulin, the hormone that helps move sugar from the blood into cells. When insulin stops working properly, we speak of insulin resistance, which is a precursor to type 2 diabetes.
It was the first evidence ever that a small peptide encoded in mitochondrial DNA could affect the metabolism of the entire body.
What Happens During Exercise
The study that sparked the most interest in MOTS-c was published in 2021 in Nature Communications. In it, researchers combined experiments in humans with experiments in mice.
The human experiment: Healthy young men who didn't usually exercise much rode a stationary bike. The researchers took muscle and blood samples before the ride, during it, after it and after four hours of rest. According to the university where the research was carried out, the results showed that:
- in the muscles, MOTS-c levels rose roughly twelvefold after exercise and still hadn't fully dropped after the rest period,
- in the blood, levels rose by about half and returned to baseline after rest.
So the body produces MOTS-c in large amounts during physical activity. This supports the idea that it is one of the signals through which the benefits of exercise show up at the cellular level.
The mouse experiment: The researchers then gave MOTS-c to mice of different ages: young, middle-aged and old (22 months, which they say corresponds to a person over 65). After treatment, the oldest mice could run roughly twice as far on a treadmill as before, and they even outran untreated middle-aged mice. The authors report that MOTS-c improved both the physical fitness and the overall health of the old mice.
Because of these results, MOTS-c is described as a substance that mimics some of the effects of exercise. It obviously can't replace exercise, but it helps explain why physical activity is so beneficial for the body.
Muscles: Easing the Brakes on Growth
Another 2021 study also focused on muscles. It looked at a protein called myostatin, which slows down muscle growth in the body. The more myostatin there is, the harder it is to build and maintain muscle mass.
- In mice on a high-fat diet, MOTS-c helped prevent the muscle loss that often comes with obesity.
- It lowered myostatin levels by about 40%.
- In humans, the researchers found that people with more MOTS-c tend to have less myostatin.
In humans, this is so far only an observed association, not proof that one causes the other. Still, it is an interesting lead for research into age-related muscle loss, which doctors call sarcopenia.
Bones: Slower Loss
Research has also extended to bones. Scientists used mice whose ovaries had been removed. This lowered their estrogen levels, and they began losing bone mass much as women do after menopause. The mice then received MOTS-c for 12 weeks.
Bone scans showed that MOTS-c reduced bone loss. The researchers also found out why: the peptide slowed the formation of the cells that break down bone (osteoclasts). Once again, it did so through the AMPK enzyme. The authors therefore describe MOTS-c as an interesting candidate for further research into osteoporosis treatment.
The Japanese Connection: Genetics and Longevity
Japan has one of the highest life expectancies in the world. Scientists were therefore intrigued that some people in East Asia carry a small variation in their mitochondrial DNA that changes one of the 16 amino acids in MOTS-c.
- In 2015, a Japanese-Spanish team put forward the hypothesis that this variation might be linked to the longevity of the Japanese.
- Six years later, another team tested it using data from more than 27,000 people of Japanese descent. The result was not what anyone expected. Men carrying this variation were more likely to have type 2 diabetes, especially if they were physically inactive. No such link was seen in women.
- On top of that, the altered MOTS-c worked less well than the usual version in experiments with mice and cells. And among people who lived to 100, the variation was no more common than in anyone else.
So the original hypothesis was not confirmed. The study did, however, deliver another valuable insight: a properly functioning MOTS-c appears to play a role in how the human body processes sugar, and its effect may be linked to how much we move.
First Steps in Humans
The animal findings also caught the attention of pharmaceutical research. The US biotech company CohBar developed CB4211, a modified version of MOTS-c, as a potential treatment for obesity and fatty liver disease. It was the very first substance derived from a mitochondrial peptide to be tested in humans.
Results from the first phase of clinical testing were released in August 2021:
- the study included 65 healthy volunteers and 20 people with obesity and fatty liver disease,
- according to the report, the substance was well tolerated, with no serious side effects,
- compared with placebo, liver test results improved and blood sugar dropped, while body weight showed a downward trend.
It was a small, short study. But it was a first step toward testing what we know about MOTS-c in humans.
Timeline of MOTS-c Research
| Year | What happened |
|---|---|
| 2001 | Humanin, the first known mitochondrial-derived peptide, is discovered. |
| 2015 | Lee and colleagues describe MOTS-c and its effect on metabolism and insulin sensitivity in mice. |
| 2015 | A hypothesis emerges linking a Japanese variant of MOTS-c to longevity. |
| 2018 | Scientists find that MOTS-c moves into the cell nucleus under stress and switches on protective genes. |
| 2021 | Study in Nature Communications: exercise increases MOTS-c in muscles, and old mice show improved fitness. |
| 2021 | MOTS-c lowers myostatin in mice and protects muscles from wasting. |
| 2021 | A study of more than 27,000 people links the Japanese variant of MOTS-c to diabetes in men. |
| 2021 | Results are published from the first human study of a modified version of MOTS-c (CB4211). |
| 2025 | The World Anti-Doping Agency (WADA) adds MOTS-c to its list of prohibited substances. |
Why MOTS-c Matters to Science
- It changed how we see mitochondria. It showed that they don't just make energy but also send signals that control how cells behave.
- It helps explain why exercise is healthy. It is one of the molecules through which the benefits of exercise show up in the body.
- It's linked to aging. Its blood levels decline with age, and it affected physical fitness in old animals.
- It has a broad reach. Research covers sugar, fat, muscles, bones and how well cells withstand stress.
- It inspires drug development. A substance derived from MOTS-c has already gone through its first tests in humans.
Frequently Asked Questions
What exactly is MOTS-c?
It's a small peptide made up of 16 amino acids that the body produces in its mitochondria. It acts as a signal that helps cells adjust how they manage energy.
Does everyone produce MOTS-c?
Yes. MOTS-c is naturally present in the body and can be measured in the blood. Its levels change, though: they rise during exercise and fall as we get older.
How is MOTS-c related to exercise?
During exercise, the muscles produce large amounts of it. In a 2021 study, its level in muscle rose roughly twelvefold after a ride on a stationary bike.
Why is MOTS-c discussed in connection with aging?
Because its levels decline with age, and in studies on old mice it improved physical fitness and overall health. That's why scientists are studying it as one of the factors that influence how well we age.
What's the difference between MOTS-c and humanin?
Both are mitochondrial-derived peptides. Humanin was discovered earlier, in 2001, and is studied mainly in connection with protecting cells. MOTS-c was discovered in 2015, and research on it focuses mainly on metabolism and muscles.
What is AMPK?
An enzyme that monitors the amount of energy in a cell. When energy runs low, it prompts the cell to burn more sugar and fat. MOTS-c activates it, which explains most of its effects.
Is MOTS-c on the list of substances banned for athletes?
Yes. Since January 1, 2025, the World Anti-Doping Agency (WADA) has listed it among substances prohibited for athletes at all times, both in and out of competition.
What does “research use only” mean?
It means the substance is intended for laboratory and scientific research. It is not a medicine or a dietary supplement and is not intended for human use.
Why is a certificate of analysis important for research peptides?
A certificate of analysis (CoA) confirms that the package really contains the substance stated on the label and shows how pure it is. It usually includes the results of two laboratory methods: chromatography (HPLC), which shows purity, and mass spectrometry (MS), which confirms that it's the right molecule. Without it, research results wouldn't be reliable.
Is MOTS-c approved as a medicine?
No. MOTS-c is not approved as a medicine in the United States (FDA), the European Union (EMA) or the United Kingdom (MHRA). It is available only as a research compound. Its modified version, CB4211, has so far only completed the first phase of clinical testing.
Summary
MOTS-c is a tiny peptide that the body makes in its mitochondria and produces more of during exercise. Its discovery showed that mitochondria don't just make energy but also send messages to the rest of the cell. Animal studies suggest that MOTS-c helps the body process sugar better, protects muscles and bones and improved physical fitness in old mice. In humans, we know that its levels rise with physical activity and fall with age.
Most of what we know so far comes from laboratory and animal studies, so research still has a long way to go. Even now, though, MOTS-c is one of the most interesting discoveries in aging research, and it helps explain why regular exercise matters so much for the body.
You'll find an overview of MOTS-c and other research peptides on our research compounds page: MOTS-c.
Sources
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- Kim KH, Son JM, Benayoun BA, et al. “The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.” Cell Metabolism, 2018.
- Reynolds JC, Lai RW, Woodhead JST, et al. “MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.” Nature Communications, 2021;12:470: doaj.org
- University of Southern California – press release on Reynolds et al. 2021: today.usc.edu
- Kumagai H, Coelho AR, Wan J, et al. “MOTS-c reduces myostatin and muscle atrophy signaling.” American Journal of Physiology – Endocrinology and Metabolism, 2021. DOI: 10.1152/ajpendo.00275.2020
- Study of MOTS-c in an ovariectomized mouse model of osteoporosis (inhibition of osteoclast formation via AMPK), Elsevier: infona.pl
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- Zempo H, Kim SJ, Fuku N, et al. “A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.” Aging (Albany NY), 2021;13(2):1692–1717: static-site-aging-prod.impactaging.com
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- Longevity.Technology – results of the CB4211 phase 1a/1b study (August 2021): longevity.technology
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- ISSF – WADA 2025 Prohibited List (inclusion of MOTS-c): issf-sports.org