MOTS-c
Also known as: MOTS-c; MOTS-C; Mitochondrial ORF of the 12S rRNA type-c; Mitochondrial Open Reading Frame of the 12S rRNA-c
5 notable studies · 7 references
TLDR
MOTS-c is studied for metabolic regulation, mitochondrial signaling, exercise adaptation, skeletal-muscle function, and aging, with promising experimental evidence but limited human evidence for externally administered MOTS-c.
Research Supports
- Studied for its role in metabolic regulation and insulin sensitivity
- Investigated for involvement in exercise adaptation and physical performance
- Studied as a mitochondrial signaling molecule involved in cellular energy sensing
- Investigated for a possible role in age-related physical decline
- Researched in skeletal-muscle maintenance and myostatin/atrophy pathways
Observations Reported in Research
- Administered MOTS-c improved insulin sensitivity and reduced diet- and age-related insulin resistance in mice (Lee et al., 2015)
- Exercise increased endogenous MOTS-c in skeletal muscle and circulation in young male participants (Reynolds et al., 2021)
- Intermittent MOTS-c treatment initiated late in life improved physical capacity in older mice (Reynolds et al., 2021)
- A single MOTS-c dose improved running time and distance in untrained mice (Hyatt, 2022)
- Circulating MOTS-c was associated with aerobic exercise capacity in marathon runners vs sedentary participants (2025 study)
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Mitochondrial-derived peptide (MDP); 16-amino-acid peptide encoded within mitochondrial DNA
MOTS-c is a small peptide encoded by mitochondrial DNA that researchers are studying for its role in metabolic regulation, cellular stress responses, skeletal muscle function, exercise adaptation, and healthy aging. Much of the evidence for administering MOTS-c comes from laboratory and animal studies, while human research has primarily examined naturally occurring MOTS-c and its relationship with exercise and metabolic physiology.
What Is MOTS-c?
MOTS-c is a naturally occurring 16-amino-acid peptide produced from genetic information within the mitochondrial genome. Mitochondria are best known for helping cells produce energy, but research increasingly suggests that they also act as signaling centers. MOTS-c is one example of that signaling role: it appears capable of communicating information about cellular energy and metabolic stress to other parts of the cell. Researchers first reported MOTS-c in 2015 while investigating mitochondrial signaling and metabolic homeostasis. Since then, it has attracted interest in areas including glucose metabolism, skeletal muscle, exercise, obesity, age-related physical decline, and mitochondrial function.
What Are Researchers Studying?
Metabolic regulation and insulin sensitivity
Researchers are investigating how MOTS-c affects glucose handling, insulin sensitivity, and the way skeletal muscle responds to metabolic stress. Early animal research found that administered MOTS-c improved metabolic measures in mouse models of diet- and age-related insulin resistance.
Exercise and physical performance
MOTS-c appears to respond to exercise and has been studied as part of the signaling relationship between mitochondria and skeletal muscle. Human studies have measured changes in naturally occurring MOTS-c around exercise, while animal studies have examined whether administered MOTS-c can influence exercise capacity and adaptation.
Mitochondrial function and cellular energy
Researchers are studying MOTS-c as a mitochondrial signaling molecule involved in cellular energy sensing. Recent experimental work has examined its effects on mitochondrial efficiency, oxidative stress, and pathways involving AMPK and PGC-1α.
Aging and physical decline
Because mitochondrial function and metabolic flexibility often change with age, researchers have investigated whether MOTS-c participates in age-related changes in physical capacity. Animal studies have reported improved physical performance after MOTS-c administration in both younger and older mice.
Skeletal muscle maintenance
MOTS-c is also being investigated in muscle biology, including myostatin signaling, muscle atrophy pathways, and cellular responses to metabolic stress. This remains an emerging research area with substantial preclinical evidence.
How Does It Work?
MOTS-c appears to function as a metabolic signaling peptide. Early research found that MOTS-c can influence folate and purine metabolism and activate AMP-activated protein kinase (AMPK), an important cellular energy sensor. Under metabolic stress, MOTS-c has also been reported to move into the nucleus, where it may influence the expression of genes involved in stress adaptation and metabolism. Research has additionally connected MOTS-c signaling with PGC-1α, a regulator involved in mitochondrial biology and metabolic adaptation. Rather than acting through one simple receptor-and-response pathway, MOTS-c appears to participate in a broader network connecting mitochondrial status, cellular energy sensing, nuclear gene expression, and skeletal muscle metabolism. The details of that network are still being worked out.
What Does the Research Show?
Human research
Human research confirms that MOTS-c occurs naturally and is associated with aspects of exercise and metabolic physiology. A 2021 study involving young male participants reported increases in endogenous MOTS-c in skeletal muscle and circulation following exercise. Other human studies have examined circulating MOTS-c in relation to endurance exercise, muscle strength, body composition, and metabolic status. A 2025 study comparing marathon runners with sedentary participants reported associations between circulating MOTS-c and aerobic exercise capacity. Most human research has measured naturally occurring MOTS-c rather than testing administered MOTS-c as an intervention.
Animal research
Animal research currently provides much of the experimental evidence surrounding MOTS-c administration. The original 2015 study reported that MOTS-c treatment improved insulin sensitivity and protected mice against diet-induced obesity and age- and diet-associated insulin resistance. Subsequent mouse studies have explored physical performance, metabolic stress, skeletal muscle function, mitochondrial biology, and aging. A 2021 study reported improved physical capacity in young, middle-aged, and older mice and found that intermittent treatment initiated late in life improved measures of physical capacity. A 2022 study reported improved running time and distance after a single MOTS-c administration in untrained mice. More recent experimental work has continued investigating how MOTS-c affects skeletal-muscle mitochondrial function and has implicated AMPK and PGC-1α signaling.
In-vitro research
Cell-based research suggests that MOTS-c can influence metabolic and stress-response pathways, including AMPK signaling, nuclear gene expression, glucose metabolism, and mechanisms involved in skeletal muscle maintenance. Research in cultured cells has also explored MOTS-c under metabolic stress and conditions associated with muscle atrophy.
Notable Studies
The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance
in-vitroThis foundational study identified MOTS-c as a 16-amino-acid mitochondrial-derived peptide and investigated its role in metabolic regulation. Cellular experiments linked MOTS-c with the folate-purine pathway and AMPK activation. In mice, MOTS-c treatment improved insulin sensitivity and protected against high-fat-diet-induced obesity and age- and diet-associated insulin resistance.
Limitations: The intervention findings were primarily preclinical. The study included evidence that MOTS-c exists in human circulation, but it did not establish the safety, efficacy, pharmacokinetics, or clinical effects of administering MOTS-c to humans. Results from cellular and mouse models therefore cannot be assumed to translate directly to human outcomes.
View publication →MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis
humanResearchers investigated the relationship between MOTS-c, exercise, skeletal muscle, metabolic stress, and age-related physical decline. Human experiments found exercise-associated changes in endogenous MOTS-c. In mice, administered MOTS-c increased physical performance across young, middle-aged, and older animals. Intermittent treatment initiated late in life also increased physical capacity.
Limitations: The study combined different types of evidence. The human portion primarily examined naturally occurring MOTS-c in response to exercise, whereas much of the evidence for externally administered MOTS-c came from mice. The mouse intervention results therefore do not demonstrate that administered MOTS-c improves physical performance or aging-related outcomes in humans.
View publication →MOTS-c Increases in Skeletal Muscle Following Long-Term Physical Activity and Improves Acute Exercise Performance After a Single Dose
animalThe study investigated the relationship between physical activity and skeletal-muscle MOTS-c expression in rodents. Several weeks of voluntary running increased MOTS-c protein expression in multiple skeletal muscles. The study also examined acute MOTS-c administration and reported improved running time and distance in untrained mice following a single dose.
Limitations: The experiments were conducted in rodents rather than humans. Exercise-performance findings after MOTS-c administration therefore cannot establish performance effects in people. The study also does not establish human safety, appropriate exposure, or long-term outcomes.
View publication →Endurance Training Enhances Skeletal Muscle Mitochondrial Respiration by Promoting MOTS-c Secretion
humanResearchers investigated the relationship among endurance exercise, MOTS-c, and skeletal-muscle mitochondrial respiration. The work connected endurance training with MOTS-c-related changes and mitochondrial respiratory function and provided additional evidence supporting a relationship between MOTS-c signaling and exercise-associated mitochondrial physiology.
Limitations: The study used multiple experimental approaches, and mechanistic or intervention findings from animal models should not be treated as proof of the effects of administered MOTS-c in humans. Associations observed in exercising humans also do not establish that administering MOTS-c reproduces exercise-related adaptations.
View publication →MOTS-c Improves Intrinsic Muscle Mitochondrial Bioenergetic Health and Efficiency in a PGC-1α/AMPK-Dependent Manner
animalResearchers investigated whether MOTS-c directly affects skeletal-muscle mitochondrial function. In two transgenic mouse models, administered MOTS-c improved mitochondrial bioenergetic performance through mechanisms dependent on PGC-1α and AMPK. Treatment also reduced mitochondrial reactive oxygen species emission and related protein damage. In the human exercise component, researchers did not find evidence from arterio-venous measurements that exercising skeletal muscle was the source of increased circulating MOTS-c.
Limitations: The experimental administration and mechanistic findings were primarily obtained in mouse models. The human portion addressed endogenous MOTS-c during exercise rather than testing MOTS-c administration as a therapeutic intervention. The study therefore does not establish clinical benefits, safety, or effectiveness of administered MOTS-c in humans.
View publication →What We Still Don't Know
Researchers have not established whether externally administered MOTS-c produces the metabolic, exercise, body-composition, mitochondrial, or healthy-aging effects in humans that have been reported in experimental models. Important unanswered questions include: Whether administered MOTS-c produces meaningful clinical effects in humans Human pharmacokinetics and bioavailability Short- and long-term safety Appropriate exposure levels for controlled clinical investigation Whether effects observed in mice translate to humans Which tissues contribute most to circulating MOTS-c How endogenous MOTS-c differs biologically from externally administered MOTS-c The complete signaling pathway and molecular targets responsible for its effects Whether associations with exercise, aging, or metabolic health are causal The gap between promising mechanistic/preclinical findings and controlled human intervention evidence remains substantial.
Recent publications
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Sources & References
- Lee C, Zeng J, Drew BG, et al. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metabolism. 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009.
- 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(1):470. doi:10.1038/s41467-020-20790-0.
- Acute Endurance Exercise Stimulates Circulating Levels of Mitochondrial-Derived Peptides in Humans. Journal of Applied Physiology. 2021.
- Hyatt JPK. MOTS-c Increases in Skeletal Muscle Following Long-Term Physical Activity and Improves Acute Exercise Performance After a Single Dose. Physiological Reports. 2022;10(13). doi:10.14814/phy2.15377.
- Wan W, Zhang C, Danielsen M, et al. Mitochondria-Derived Peptide MOTS-c: Effects and Mechanisms Related to Stress, Metabolism and Aging. Journal of Translational Medicine. 2023;21(1):36. doi:10.1186/s12967-023-03885-2.
- Feng Y, Rao Z, Tian X, et al. Endurance Training Enhances Skeletal Muscle Mitochondrial Respiration by Promoting MOTS-c Secretion. Free Radical Biology and Medicine. 2025;227:619–628. doi:10.1016/j.freeradbiomed.2024.12.038.
- Gudiksen A, Hansen CC, van der Stede T, et al. MOTS-c Improves Intrinsic Muscle Mitochondrial Bioenergetic Health and Efficiency in a PGC-1α/AMPK-Dependent Manner. Free Radical Biology and Medicine. 2026;246:682–696. doi:10.1016/j.freeradbiomed.2026.01.002.
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