MOTS-c: a mitochondrial-derived peptide, mechanisms of action and scientific evidence

Note regarding scientific evidence: The article presents the results of experimental and observational studies. Most of the data regarding the activity of MOTS-c come from cell and animal studies. The observed dependencies in humans do not confirm the therapeutic efficacy or safety of this peptide. Experimental doses and concentrations are presented solely as an element of the study description, and not as instructions for use in humans.

MOTS-c (Mitochondrial ORF of the 12S rRNA type-C) is a relatively recently characterized peptide of mitochondrial origin. It consists of 16 amino acids and the information about its structure is stored in the region of the 12S rRNA of the mitochondrial genome [1]. Under normal physiological conditions, MOTS-c is primarily found in mitochondria. However, in response to metabolic stress, it can migrate to the cell nucleus, where it influences the expression of genes responsible for maintaining cellular homeostasis [1].

Although the genetic information regarding MOTS-c is located in mitochondrial DNA, the peptide itself is synthesized in the cytoplasm, not within the mitochondria [1]. This is due to differences between mitochondrial and cytoplasmic genetic codes that allow the export of polyadenylated MOTS-c transcript to the cytoplasm and its translation. The amino acid sequence of MOTS-c, particularly the first 11 amino acid residues, exhibits a high degree of evolutionary conservation across different species [1].

MOTS-c was identified during studies of mitochondrial signals involved in metabolism regulation. Subsequent experiments showed its involvement in the regulation of glucose metabolism and insulin sensitivity, primarily through protein kinase-activated AMP-dependent signaling pathways (AMPK) [1].

It was also observed that the concentration of MOTS-c in the blood may vary depending on age, metabolic status, and the characteristics of the studied population. This suggests that the peptide may participate in the broader regulation of the entire body's metabolism.

The metabolic and protective role of MOTS-c in diabetes and metabolic stress

Experimental studies analyzed the potential role of MOTS-c in energy metabolism and the body's response to metabolic stress. Improvement in glucose utilization, increased insulin sensitivity, and beneficial changes in lipid metabolism were observed in various cell and animal models. In some experiments, a reduction in body weight gain and tissue damage were also noted.

The observed effects were not limited to regulating metabolism; they also affected the heart, liver, pancreas, the nervous system, and the immune response, particularly in models of diabetes and age-related changes.

At the molecular level, MOTS-c acts on pathways responsible for detecting energy availability and responding to cellular stress. These mechanisms may help cells adapt to excess nutrients, oxidative stress, and inflammation.

Overall, the results of the study indicate that MOTS-c may participate in the regulation of the body’s metabolic resistance and trigger certain biological responses resembling adaptations observed during physical activity. However, this does not mean that such an effect has been clinically confirmed in humans.

Lee et al. (2015): identification of MOTS-c and regulation of metabolism

Lee and colleagues (2015) identified MOTS-c as a small peptide encoded by mitochondrial DNA [2]. It consists of 16 amino acids and its sequence is encoded within mitochondrial RNA.

The researchers studied the effects of MOTS-c in muscle cells and in mice exposed to stress associated with aging and a high-fat diet.

In muscle cells, MOTS-c limited the activity of certain metabolic pathways and activated AMPK — an enzyme that acts as a cellular energy sensor and helps regulate the use of glucose.

In mice, MOTS-c prevented the development of insulin resistance associated with aging and a high-fat diet. The animals receiving the peptide gained less weight and accumulated less fat tissue. They also showed better glycemic control and greater metabolic flexibility, which is the body's ability to adapt the way it obtains energy to the current conditions.

The results suggest that MOTS-c may support the maintenance of proper metabolism by regulating energy processes that occur primarily in the muscles.

Yin et al. (2022): MOTS-c in the model of gestational diabetes

Yin and colleagues (2022) evaluated the effect of MOTS-c in gestational diabetes, a disorder characterized by elevated blood glucose levels during pregnancy [3].

Researchers used pregnant mice fed a high-fat diet, in which mild chemical stress was also induced to reproduce the disease characteristics. MOTS-c was administered daily throughout the entire gestation period.

A reduction in fasting glucose levels and a decrease in excessive blood insulin levels were observed. Insulin sensitivity also improved.

In experiments on muscle cells, MOTS-c increased glucose uptake, facilitating its penetration into the cells. The peptide also reduced damage to the cells of the pancreas that produce insulin and helped maintain their ability to secrete this hormone.

Furthermore, more favorable pregnancy outcomes were observed. In animals receiving MOTS-c, excessive fetal growth was less frequently observed, and neonatal mortality was lower.

The results suggest that MOTS-c can affect both the metabolism of the mother and the development of the fetus in an experimental model of gestational diabetes. However, they do not provide evidence of the safety or efficacy of using the peptide in pregnant women.

Kim et al. (2018): Transferring MOTS-c to the cell nucleus

Kim and colleagues (2018) investigated the way MOTS-c works inside cells during metabolic stress [4].

When the availability of glucose or other nutrients was limited, MOTS-c moved from the mitochondria into the cell nucleus, where gene activity is regulated.

This process depended on the activation of AMPK.

Upon reaching the core of MOTS-c, it influenced the expression of genes related to metabolism, stress adaptation, and antioxidant protection.

The peptide also interacted with NRF2 — an important regulator of the cell's defense mechanisms against oxidative damage.

MOTS-c participated in the activation of genetic programs that help cells cope with metabolic and oxidative stress.

The results indicate that MOTS-c may be an element of direct communication between mitochondria and the cell nucleus, enabling cells to adapt quickly to energy shortages.

Tang et al. (2023): the effect of MOTS-c on the heart in type 2 diabetes

Tang and colleagues (2023) analyzed the effect of MOTS-c in rats with type 2 diabetes caused by a high-fat diet and low doses of streptozotocin [5].

The mice were administered MOTS-c in injections at a dose of 0.5 mg/kg body weight per day for eight weeks. The results were compared with the effects of aerobic training and the combination of MOTS-c with exercise.

MOTS-c improved the structure and function of the heart. Microscopic analysis showed less damage to the fibers of the heart muscle and mitochondria.

An improvement in glucose and lipid metabolism was also observed.

The peptide enhanced the heart's antioxidant mechanisms by increasing the activity of superoxide dismutase and catalase and by increasing the level of glutathione. At the same time, it reduced the level of malondialdehyde, which is an indicator of oxidative damage.

At the molecular level, MOTS-c activated the AMPK and NRF2 signaling pathways.

The strongest protective effects occurred in the group in which MOTS-c was combined with aerobic exercise.

The results suggest that MOTS-c can reproduce some of the biological effects of physical exercise and limit heart damage associated with diabetes in an animal model.

Chen et al. (2025): MOTS-c and liver fibrosis associated with diabetes

Chen and colleagues (2025) studied the effect of MOTS-c in a liver fibrosis model associated with type 2 diabetes [6].

Fibrosis develops as a result of long-term damage to liver tissue and excessive accumulation of extracellular matrix components, including collagen.

Researchers used rats with diabetes and already developed fibrosis of the liver. Three experimental approaches were compared: administration of MOTS-c, aerobic training, and a combination of both interventions.

In rats with diabetes, liver dysfunction and significant accumulation of collagen were observed.

MOTS-c improved the structure of the liver tissue and reduced fibrosis. Aerobic exercise provided similar effects, while the combination of both interventions yielded the greatest improvement.

In the groups that underwent interventions, the indicators of liver function also improved.

At the molecular level, MOTS-c activated the Keap1–Nrf2 pathway, which enhances cellular antioxidant mechanisms. This led to a reduction in the amount of reactive oxygen species in liver cells.

At the same time, the peptide inhibited the TGF-β1–Smad2/3 pathway, which is involved in the process of fibrous tissue formation.

Cellular studies confirmed these observations. Increasing the level of MOTS-c enhanced the expression of antioxidant genes and reduced the activity of genes related to fibrosis. Blocking MOTS-c reversed these effects.

The results suggest that MOTS-c may limit liver fibrosis in diabetes by enhancing antioxidant protection and inhibiting processes leading to the formation of scars. These mechanisms partially resembled the effects of aerobic exercise.

Pham et al. (2025): cardiac energy metabolism

Pham and colleagues (2025) tested whether MOTS-c could improve energy production in the hearts of rats with type 2 diabetes [7].

Diabetes was induced by a high-fat diet combined with low doses of streptozotocin. Subsequently, the animals were given daily injections of MOTS-c at a dose of 15 mg/kg body weight for three weeks.

In rats with diabetes who did not receive the peptide, there were elevated blood glucose levels, disturbances in its metabolism, and hypertrophy of the heart muscle.

The mitochondria of the heart cells showed a reduced ability to use oxygen during energy production, indicating a reduced metabolic efficiency.

Administration of MOTS-c reduced fasting glucose levels and limited cardiac hypertrophy.

At the cellular level, improvements in mitochondrial respiration and oxygen utilization were observed.

The peptide also limited the breakdown of ATP under conditions of oxygen deficiency, helping to maintain cellular energy reserves.

The level of reactive oxygen forms slightly increased, but remained within the range interpreted by researchers as a normal adaptive response.

The results suggest that MOTS-c can improve mitochondrial performance and cardiac energy metabolism in an animal model of type 2 diabetes.

Kim et al. (2019): changes in blood circulating metabolites

Kim and colleagues (2019) analyzed the effect of MOTS-c on metabolic markers present in the blood of mice with diet-induced obesity [8].

The mice were administered MOTS-c in injections, and then plasma metabolites were analyzed using a broad screening study, without prior restriction of the analysis to selected compounds.

MOTS-c reduced the activity of several metabolic pathways that are usually increased in obesity and diabetes.

This concerned, among other things, the metabolism of sphingolipids, monoacylglycerols and dikarboxylanes.

These pathways are associated with fat accumulation and metabolic stress.

At the same time, MOTS-c increased the breakdown of fatty acids, reduced lipid accumulation, and improved insulin sensitivity. Improved regulation of blood glucose levels was also observed.

The results suggest that MOTS-c can alter the profile of circulating metabolites in the blood in a way that favors more efficient energy utilization and improved insulin response, which in the studied model limited metabolic damage associated with obesity.

Yang et al. (2021): the interaction between MOTS-c and physical activity

Yang and colleagues (2021) investigated how MOTS-c and physical activity interact in the regulation of glucose metabolism [9].

Special attention was paid to the AMPK–PGC-1α pathway, which is involved in controlling energy production in muscles and the formation of new mitochondria.

In experiments on muscle cells, inhibition of AMPK led to a reduction in the levels of PGC-1α and MOTS-c.

Lowering the level of PGC-1α also limited the expression of MOTS-c.

In turn, increasing the level of PGC-1α or adding recombinant MOTS-c increased the level of endogenous MOTS-c, indicating the existence of a positive feedback loop.

In obese mice, the concentration of MOTS-c in the muscles and in the blood was reduced.

Running training restored the level of MOTS-c and increased the activity of PGC-1α, GLUT4 and AMPK signaling.

These changes were accompanied by an improvement in insulin sensitivity and glucose metabolism.

The results indicate that MOTS-c and physical activity can mutually enhance their effects through a common pathway regulating energy metabolism. This provides a basis for further research into their significance in insulin resistance and metabolic health.

Wu et al. (2025): Cardiomyopathy associated with type 1 diabetes

Wu and colleagues (2025) investigated whether MOTS-c can protect the heart in a model of cardiomyopathy associated with type 1 diabetes [10].

Diabetic cardiomyopathy is a disorder in which long-term diabetes leads to changes in the structure and function of the heart muscle.

In mice, type 1 diabetes was induced using streptozotocin. After the disease developed over 12 weeks, MOTS-c was administered continuously using subcutaneous osmotic pumps.

In mice with diabetes, there was an enlargement of the heart chambers, a weakening of the ability to pump blood, and an abnormal remodeling of the heart muscle.

Administration of MOTS-c improved overall heart function and cell function.

The structure of the heart muscle was better preserved, and the tissue damage was less severe.

Microscopic analysis showed a reduction in fiberization and an improvement in tissue integrity.

At the molecular level, diabetes weakened AMPK signaling and increased the severity of inflammatory processes in the heart.

MOTS-c again activated AMPK and reduced the levels of inflammatory markers.

The results suggest that long-term administration of MOTS-c may protect the heart in an animal model of diabetes by improving energy balance and reducing inflammation.

Kong et al. (2021): protection of pancreatic cells in autoimmune diabetes

Kong and colleagues (2021) investigated whether MOTS-c can protect insulin-producing pancreatic cells from damage in the course of autoimmune diabetes [11].

NOD mice, an animal model of type 1 diabetes that develops as a result of an immune system attack on pancreatic cells, were used.

Administration of MOTS-c delayed or prevented the increase in blood glucose levels.

Analysis of pancreatic tissue showed a significantly lower influx of immune cells into the insulin-producing islets. This indicated a reduction in autoimmune damage.

In experiments involving the transfer of immune cells, T lymphocytes taken from mice receiving MOTS-c caused diabetes less frequently after transfer to mice with immunodeficiency.

This indicated that MOTS-c directly changed the behavior of T lymphocytes.

Further analyses showed that the peptide influenced the activation and metabolism of these cells by regulating the TCR–mTORC1 pathway, responsible for controlling their activity and energy utilization.

MOTS-c helped T lymphocytes cope with metabolic stress and limited their excessive activation.

Lower levels of MOTS-c were found in blood samples of people with type 1 diabetes than in healthy people.

In laboratory studies, the peptide also limited the activation of human T lymphocytes under stress conditions.

The results suggest that MOTS-c can protect pancreatic cells by limiting harmful immune responses. They also indicate the need for further research into its potential significance in autoimmune diabetes.

Fu et al. (2024): oxidative stress and inflammation in the heart muscle

Fu and colleagues (2024) investigated whether MOTS-c can reduce heart damage caused by inflammation and oxidative stress associated with diabetes [12].

Diabetes was induced in rats using a diet rich in sugar and fat, followed by small doses of streptozotocin.

The animals were administered MOTS-c by injection at a dose of 0.5 mg/kg body weight per day for eight weeks.

In rats with diabetes, elevated levels of harmful reactive oxygen species were observed, increased expression of TXNIP, and activation of the NLRP3 inflammasome, which plays an important role in the development of inflammation.

Administration of MOTS-c reduced oxidative stress and decreased the levels of TXNIP and NLRP3 in the heart tissue.

The inflammation of the heart muscle was less severe, and the tissue structure improved compared to rats with diabetes that did not receive the peptide.

The results suggest that MOTS-c may protect the heart in diabetes by inhibiting a key inflammatory pathway activated by oxidative stress.

Lu et al. (2019): metabolism after estrogen loss

Lu and colleagues (2019) investigated MOTS-c in a model of metabolic deterioration associated with menopause caused by estrogen deficiency [13].

The ovaries were removed from female mice, which led to an increase in body weight, accumulation of adipose tissue, an exacerbation of inflammation, and the development of insulin resistance.

Administration of MOTS-c prevented excessive weight gain and helped maintain insulin sensitivity.

The peptide increased the activity of brown adipose tissue, which is involved in the burning of energy substrates and the production of heat.

This led to an increase in the total energy expenditure.

In white adipose tissue, MOTS-c limited fat storage and the influx of immune cells, reducing the severity of inflammation.

The concentration of fatty acids in the blood also decreased, and the amount of fat accumulated in the liver was lower.

At the molecular level, MOTS-c activated AMPK, an important regulator of energy and lipid metabolism.

Blocking AMPK limited the beneficial effects observed after administration of MOTS-c, confirming the important role of this pathway.

The results suggest that MOTS-c may contribute to maintaining the proper function of adipose tissue and reducing metabolic disorders associated with estrogen deficiency.

Li et al. (2022): the effect of MOTS-c and the effects of aerobic training

Li and colleagues (2022) analyzed the effect of MOTS-c on diabetes-related heart disease and examined whether the observed effects resembled the effects of aerobic exercise [14].

Rats with type 2 diabetes caused by a diet rich in fat and sugar and with low doses of streptozotocin were used.

The animals were given either MOTS-c or subjected to aerobic exercise training. Subsequently, the structure and function of the heart and the expression of genes were evaluated.

In rats with diabetes, a weakening of the heart’s function and an abnormal remodeling of the heart muscle were observed.

Both MOTS-c and physical exercise significantly improved the heart structure and restored its ability to pump blood.

The tightness of the cell walls decreased, the size of the heart chambers increased, and the contraction weakened.

The analysis of gene expression showed that MOTS-c reproduced many molecular effects associated with physical exertion.

They included reducing inflammation, reducing heart cell death, enhancing the formation of new blood vessels, and improving the migration and growth of endothelial cells that line the vessels.

Importantly, MOTS-c activated the NRG1–ErbB4 signaling pathway, which is involved in the survival and repair of heart cells and the maintenance of vascular health.

Overall, the results suggest that MOTS-c can improve heart function in diabetes by activating certain protective mechanisms that are also activated during aerobic exercise.

Figure 1. Metabolic and protective effects of MOTS-c in diabetes and metabolic stress (based on animal studies).

Wang et al. (2023): myocardial regeneration and mitochondrial function

Wang and colleagues (2023) investigated whether MOTS-c can reduce heart damage and improve its function in rats with diabetes [15].

Diabetes was caused by a diet rich in sugar and fat combined with streptozotocin. This led to mitochondrial damage, increased cell death, and disorders in the contraction and relaxation of the heart muscle.

The mice were administered MOTS-c for eight weeks. After the end of the experiment, improvements in the structure and integrity of the mitochondria in the heart cells were observed. At the same time, both the contractile and relaxation functions improved significantly.

Gene sequencing revealed that MOTS-c influenced the activity of 47 genes associated with heart damage in the course of diabetes. These changes involved inflammation regulation, blood vessel formation, fat metabolism, and cell survival.

At the molecular level, MOTS-c limited the death of cardiac muscle cells by reducing the level of CCN1 and inhibiting the ERK1/2 pathway. This led to a reduction in the activity of EGR1, a gene regulator involved in the adverse remodeling of the heart.

The results indicate that MOTS-c can limit myocardial damage and help maintain its proper function by reducing cell death and improving mitochondrial function in an animal model of diabetes.

Kong et al. (2025): aging of pancreatic cells

Kong and colleagues (2025) analyzed whether MOTS-c could limit the age-related deterioration of the functions of the pancreatic cells that produce insulin, which plays an important role in the development of diabetes [16].

The study included old mice, mice with insulin resistance, and models of autoimmune diabetes.

In all models, aging and progression of the disease were associated with a significant decrease in the level of MOTS-c in pancreatic islets.

When aging pancreatic islets were treated with MOTS-c, cellular aging rates decreased, and gene activity shifted toward patterns characteristic of a more favorable metabolic state.

In living animals, MOTS-c improved insulin secretion and glucose tolerance in both insulin-resistant and autoimmune diabetes models.

Importantly, the peptide consistently reduced markers of cellular aging and helped preserve the structure and function of insulin-producing cells.

Samples from people showed that people with type 2 diabetes had significantly lower levels of MOTS-c in their blood than healthy people.

Overall, the results suggest that MOTS-c may limit the processes of aging of pancreatic cells and help maintain their ability to secrete insulin. However, they do not prove that administering the peptide delays the development of diabetes in humans.

Xu et al. (2024): painful diabetic neuropathy

Xu and colleagues (2024) investigated whether MOTS-c can affect diabetic neuropathic pain, which is a common and troublesome complication of diabetes associated with nerve damage [17].

In mice with streptozotocin-induced diabetes, the natural level of MOTS-c decreased significantly in both blood and spinal cord.

The animals showed elevated glucose levels, weight loss, and increased sensitivity to pain, including to light touch and high temperatures.

After taking MOTS-c, glycemic control improved, body weight stabilized, and sensitivity to pain stimuli significantly decreased.

However, blocking the AMPK pathway resulted in the disappearance of these effects, indicating its key importance.

At the molecular level, MOTS-c increased AMPK and PGC-1α activity in the spinal cord. This promoted mitochondrial regeneration, limited excessive activation of immune cells in the nervous tissue, and reduced inflammatory signals.

As a result, a smaller increase in inflammation of the nerve tissue and pain signaling was observed.

The results indicate that MOTS-c can reduce the pain symptoms of diabetic neuropathy in an animal model through improved mitochondrial function, reduced inflammation, and regulation of energy metabolism. However, the question remains to what extent these effects are independent of changes in pain-related behaviors.

MOTS-c in muscle protection, tissue regeneration and adaptation to physical exertion

The studies analyzed the potential role of MOTS-c in maintaining muscle mass, repairing tissues, and adapting the body to stress and physical activity.

Results of observational studies in humans, cellular experiments, and animal experiments suggest that MOTS-c can limit muscle atrophy, improve its properties, and help maintain strength under conditions of obesity, immobilization, aging, and metabolic stress.

In addition to muscle, the peptide was also studied for its ability to repair cell membranes, maintain bone structure, function of blood vessels, and the adaptation of the heart.

These processes involve related pathways that regulate energy metabolism, cell survival, and the stress response.

Kumagai et al. (2021): MOTS-c and loss of muscle mass

Kumagai and colleagues (2021) investigated the effect of MOTS-c on muscle loss associated with obesity, insulin resistance, and metabolic stress [18].

Scientists combined the analysis of data from humans with experiments on cells and animals.

In humans, higher levels of MOTS-c in the blood were associated with lower levels of myostatin — a protein that limits muscle growth and promotes its depletion.

In muscle cells exposed to the action of fatty acids, MOTS-c prevented their size from decreasing and helped maintain their proper structure.

Similarly, in mice with obesity caused by a diet, the peptide reduced the concentration of myostatin in the blood and improved indicators related to muscle maintenance.

At the molecular level, MOTS-c activated a signaling pathway involving CK2, PTEN, mTORC2, and AKT.

As a result, the activity of FOXO1, a gene expression regulator involved in muscle wasting processes, was inhibited.

The results suggest that MOTS-c can protect muscles by limiting myostatin signaling and inhibiting mechanisms that lead to the breakdown of muscle tissue during metabolic stress.

Kumagai et al. (2024): CK2 as a direct molecular target of MOTS-c

Continuing previous research, Kumagai and colleagues (2024) identified a direct molecular target through which MOTS-c can protect muscles [19].

Biochemical tests showed that MOTS-c physically binds to CK2 and activates this enzyme, which is involved in regulating cell survival and metabolism.

In mice, systemic administration of MOTS-c prevented muscle atrophy and increased glucose uptake by muscle tissue.

When CK2 activity was blocked, most of these effects disappeared. This indicated that CK2 activation is essential for the activity of MOTS-c.

Interestingly, MOTS-c activated CK2 in skeletal muscle, but inhibited its activity in adipose tissue. This indicated that this enzyme is regulated by the type of tissue.

The researchers also analyzed the naturally occurring MOTS-c variant in humans, labeled K14Q.

This variant was not associated with CK2 nor activated it. It also did not exhibit protective effects against muscle atrophy and metabolic disorders in the studied models.

Genetic data indicated that men carrying the K14Q variant were at greater risk of losing muscle mass and developing type 2 diabetes, especially in older age and with low physical activity.

The results support the interpretation that CK2 is an important mediator of the metabolic and protective effects of MOTS-c on the muscles.

Jia et al. (2024): repair of damaged cell membranes

Jia and colleagues (2024) discovered that MOTS-c can directly participate in the repair of damaged cell membranes, which is of significant importance for health and muscle regeneration [20].

In studies involving humans, higher levels of MOTS-c in the blood were associated with a higher mitochondrial content and higher expression of TRIM72, a protein involved in repairing damage to muscle cell membranes.

Moderate physical activity increased the release of MOTS-c and facilitated its movement to the sites of membrane damage, where it interacted with TRIM72.

In cellular experiments, MOTS-c limited membrane damage caused by mechanical stress.

However, after TRIM72 was blocked, the protective effect disappeared, indicating that the repair mechanism is dependent on this protein.

Importantly, this effect did not require AMPK activation.

MOTS-c was directly linked to the final fragment of TRIM72 and helped to quickly move this protein to the sites of damage.

At the same time, MOTS-c improved membrane repair even in animals lacking TRIM72. In this case, it was associated with the lipid PtdIns(4,5)P₂, which supports the fusion of cell vesicles.

In models of heart damage, the peptide helped maintain the integrity of the membranes and improved the function of the organ.

Overall, the results indicate that MOTS-c can support cell membrane repair both through protein-dependent mechanisms and through direct interaction with lipids.

Lecejewska et al. (2025): differences between types of muscle fibers

Lecejewska and colleagues (2025) investigated how MOTS-c affects different types of muscle cells [21].

Muscle cells with oxidative metabolism, which utilize endurance-related processes to a greater extent, were compared with glycolytic cells adapted for rapid energy acquisition.

MOTS-c was studied at concentrations considered physiologically relevant, from 10 to 100 nM.

In oxidative muscle cells, the peptide increased survival, rapidly activated ERK signaling, and supported cell differentiation by increasing the activity of important factors responsible for muscle development.

These cells used fats more efficiently and accumulated less lipids under stress conditions.

However, in the glycolytic cells of MOTS-c, survival or differentiation were not improved. Larger accumulation of lipids was observed in them.

Importantly, MOTS-c limited the proliferation of both cell types, suggesting a common role in regulating cell growth.

The results indicate that the effect of MOTS-c depends on the type of muscle fibers and may particularly favor the functioning of oxidative cells, which are essential for endurance, metabolic stability, and resistance to muscle atrophy.

Lu et al. (2019): MOTS-c and adaptation to cold

Lu and colleagues (2019) investigated whether MOTS-c can support the body's adaptation to low temperatures by increasing heat production in adipose tissue [22].

Cold exposure reduced the natural level of MOTS-c in the blood, suggesting a decrease in its availability during stress.

The researchers therefore gave the mice MOTS-c to see if it could improve their tolerance to cold.

The animals receiving the peptide tolerated the low temperature better and showed a smaller decrease in body temperature.

The accumulation of fat in the liver was also reduced, indicating an improvement in metabolic stability.

At the tissue level, MOTS-c increased the activity of genes responsible for the production of heat in brown adipose tissue.

It also promoted the conversion of white adipose tissue into a form more thermogenically active. This process is referred to as brown fat.

MOTS-c also activated ERK signaling. Blocking this pathway prevented the growth of thermogenic gene expression.

The results suggest that MOTS-c may enhance adaptation to cold by increasing heat production in adipose tissue via an ERK-dependent pathway.

Li and co-authors (2025): cartilage protection in osteoarthritis

Li and colleagues (2025) analyzed whether MOTS-c can protect cartilage in osteoarthritis, whose development is associated with inflammation, mechanical load, and metabolic disorders [23].

In cell models and mouse MOTS-c, it improved mitochondrial function and reduced oxidative stress in cartilage cells.

As a result, he clearly limited pyroptosis, which is the inflammatory form of programmed cell death.

At the molecular level, MOTS-c activated Nrf2, which led to the inhibition of TXNIP and prevented the activation of the NLRP3 inflammasome — an important regulator of inflammation and cartilage damage.

The peptide reduced the levels of inflammatory cytokines and cartilage-degrading enzymes, while simultaneously promoting the regeneration of normal extracellular matrix components.

In mice with osteoarthritis, MOTS-c slowed cartilage degeneration and helped maintain joint structure.

The results suggest that MOTS-c can protect joints by improving mitochondrial function, reducing inflammation, and inhibiting cartilage breakdown.

Figure 2. Potential biological significance of MOTS-c in different tissues (based on animal studies).

Yuan et al. (2023): Adaptive increase in cardiac muscle mass

Yuan and colleagues (2023) investigated whether MOTS-c can induce cardiac effects resembling adaptation to physical exercise through the activation of pathways responsible for its physiological growth [24].

The rats received MOTS-c, participated in aerobic training, or underwent both interventions. Subsequently, the structure and function of the heart were evaluated in detail.

Both interventions increased the heart mass in a way interpreted as physiological adaptation, rather than pathological hypertrophy.

The fibers of the heart muscle became thicker and more organized.

At the same time, heart function improved. Slower heart rate, better relaxation and stronger contraction were observed.

Importantly, the pressure inside the heart at rest did not increase, which supported the interpretation that the changes were of a beneficial nature.

At the molecular level, MOTS-c and aerobic training activated the same pathway involving NRG1 and ErbB4, and reduced the expression of C/EBPβ.

Such a signaling profile favors the physiological growth of the heart muscle and improves its performance.

The results suggest that MOTS-c can mimic some of the effects of aerobic exercise by activating pathways that support proper heart adaptation.

Kumagai et al. (2024): Muscle atrophy caused by immobilization

Kumagai and colleagues (2024) examined whether MOTS-c can prevent muscle loss caused by immobilization, which reproduces the activity restriction observed after injuries in older age and during chronic diseases [25].

The male mice were immobilized for eight days. During this period, they received daily injections of MOTS-c at a dose of 15 mg/kg body weight.

Just immobilization resulted in the loss of about 15% kg of muscle mass.

However, the mice receiving MOTS-c only lost about 5% of their muscle mass.

At the molecular level, MOTS-c restored important signals related to muscle mass maintenance, including the regulation of AKT and FOXO proteins, whose activity is disrupted during muscle loss.

Additionally, it significantly reduced the levels of inflammatory markers in the blood.

The analysis of gene expression showed that MOTS-c limited the activity of pathways responsible for the formation and accumulation of fat within the muscles.

This was also confirmed by the observation of a smaller accumulation of lipids in the muscle tissue.

The results suggest that MOTS-c may protect against muscle atrophy caused by inactivity by reducing inflammation, reducing fat accumulation, and restoring signaling that favors muscle tissue maintenance.

Wei et al. (2020): vascular calcification

Wei and colleagues (2020) investigated whether MOTS-c can reduce vascular calcification and protect the heart from secondary damage [26].

In rats, vascular calcification was induced by administering vitamin D₃ and nicotine. This model also leads to adverse cardiac remodeling.

Then the animals received MOTS-c in injections at a dose of 5 mg/kg body weight per day for four weeks.

A significant reduction in vessel wall thickening was observed.

At the molecular level, MOTS-c increased AMPK activation, a pathway that supports metabolic balance and reduces inflammation.

At the same time, it reduced the expression of the angiotensin II type 1 receptor and the endothelial type B receptor. Both receptors are involved in regulating blood vessel tension, inflammatory processes, and tissue remodeling.

MOTS-c also improved the heart structure by reducing secondary changes caused by vessel occlusion.

The arterial pressure, heart rate and body mass remained stable, and no adverse effects were observed in the parameters examined.

The results suggest that MOTS-c can protect blood vessels and the heart by activating AMPK and reducing adverse vascular signaling.

Wu et al. (2023): Heart protection during sepsis

Wu and colleagues (2023) investigated whether MOTS-c can protect the heart during sepsis, a severe inflammatory state of the body that can lead to heart failure [27].

In the model of septic cardiomyopathy caused by bacterial toxin MOTS-c, the inflammatory state of the heart muscle was significantly reduced.

The levels of inflammatory markers such as IL-1β, IL-4, IL-6 and TNF-α decreased.

The concentrations of markers of heart damage in the blood, including CK-MB and cardiac troponin T, also decreased.

In addition, MOTS-c improved mitochondrial function, reduced oxidative stress, and prevented the death of heart muscle cells.

At the molecular level, it activated protective pathways AMPK, AKT and ERK, while simultaneously inhibiting inflammatory pathways such as JNK and STAT3.

Importantly, blocking AMPK resulted in the disappearance of all the protective effects of MOTS-c.

This indicated that AMPK activation is essential for the peptide's action in this model.

The results suggest that MOTS-c can protect the heart during sepsis by reducing inflammation, restoring energy balance, and preventing the loss of cells.

Ran i wsp. (2021): MOTS-c and gene therapy for Duchenne muscular dystrophy

Ran and colleagues (2021) investigated whether MOTS-c can enhance the effectiveness of gene therapy in Duchenne muscular dystrophy, a severe disease leading to progressive muscle loss [28].

Muscles from mice with muscular dystrophy were used, as well as muscle cells treated with drugs that use an exon skipping mechanism, known as PMO.

The mice received MOTS-c at a dose of 500 micrograms per dose, concurrently with PMO therapy at a dose of 12.5 mg/kg weekly for three weeks. Then, administration was continued once a month for three months.

MOTS-c increased glucose metabolism and energy production in muscle cells, creating conditions conducive to the uptake of PMO.

As a result, the activity of dystrophin in various muscles increased significantly.

In the umbilical cord, the level of dystrophin increased 25-fold compared to the treatment alone with PMO.

Muscle function also improved, and no toxicity was detected in the study.

The results suggest that MOTS-c can act as a metabolism modulator, increasing the delivery and efficacy of drugs in energy-deficient muscles. This justifies further research into its potential role as an adjuvant in the treatment of muscular dystrophy.

Hyatt (2022): MOTS-c and long-term training and physical performance

Hyatt (2022) investigated how MOTS-c responds to prolonged training and whether a single administration of a peptide can improve physical performance [29].

In mice that could voluntarily run for four to eight weeks, the level of MOTS-c increased from 1.5 to 5 times in various muscles of the lower limbs.

Elevated concentrations persisted for up to six weeks after the training session ended, indicating the long-term nature of the changes.

The increase in MOTS-c levels was closely related to an increase in mitochondrial DNA. This suggested that mitochondrial development induced by exercise also increases MOTS-c reserves.

In separate experiments, a single injection of MOTS-c at a dose of 15 mg/kg improved the short-term physical performance of untrained mice.

The race time increased by 12% minutes, and the distance covered by 15% minutes.

Furthermore, after running down the MOTS-c, it moved into the nuclei of the muscle fibers of the slow-twitch muscle, which suggested its involvement in stress adaptation.

The results indicate that MOTS-c can serve as a signal responding to physical exertion, support endurance and mitochondrial function, and help maintain metabolic resistance during periods of limited activity.

Yan et al. (2019): Bone protection against damage caused by implant wear particles

Yan and colleagues (2019) investigated whether MOTS-c can protect bones from damage caused by fine particles formed during the wear of joint implants [30].

In the mouse model, small particles of plastic caused severe inflammation and destruction of bone tissue.

However, after administration of MOTS-c, bone loss was significantly reduced and local inflammation was reduced.

At the cellular level, MOTS-c influenced signaling in bone tissue, increasing the ratio of osteoprotegerin to RANKL.

This change helps to limit excessive bone resorption.

At the same time, MOTS-c inhibited inflammatory signaling in immune cells present in bone tissue by reducing NF-κB and STAT1 activation.

Importantly, artificially increasing oxidative stress or blocking the AMPK and PGC-1α pathways resulted in a loss of the protective effect of MOTS-c.

The results suggest that the peptide may limit bone destruction caused by implant wear debris by reducing inflammation and restoring proper communication between bone cells via an AMPK-dependent pathway.

Ming et al. (2016): Bone loss associated with estrogen deficiency

Ming and colleagues (2016) investigated whether MOTS-c can prevent bone tissue loss caused by estrogen deficiency, which is one of the main factors in the development of osteoporosis after menopause [31].

The ovaries of female mice were removed, and then daily injections of MOTS-c at a dose of 5 mg/kg body weight were administered for 12 weeks.

As a result, the volume and structure of the bones were better preserved, which was confirmed using detailed imaging of the bone architecture.

In cell studies, MOTS-c significantly reduced the formation of osteoclasts, which are the cells responsible for the breakdown of bone tissue.

At the molecular level, the peptide increased the activation of AMPK, a pathway involved in maintaining the balance of bone metabolism and energy regulation.

After AMPK was blocked, the protective effect of MOTS-c on bone partially disappeared.

The results indicate that MOTS-c can limit bone loss associated with hormone deficiency by reducing bone resorption through the activation of AMPK.

Sidorenko et al. (2025): muscle protection during mechanical load release

Sidorenko and colleagues (2025) investigated whether MOTS-c can prevent muscle loss caused by mechanical load, which reproduces the conditions of immobilization, prolonged lying, aging, and microgravity [32].

Male rats were subjected to a seven-day suspension of their hind limbs. During this time, the animals received daily injections of MOTS-c.

In animals that did not receive the peptide, there was severe muscle fatigue, a decrease in the proportion of slow-twitch fibers, and a general loss of muscle tissue.

In contrast, the rats receiving MOTS-c maintained greater muscle strength and showed significantly less fatigue.

Muscle analysis confirmed the preservation of characteristics typical of slow-twitch fibers and the reduction of muscle atrophy.

At the molecular level, MOTS-c maintained important signaling responsible for protein synthesis, including Akt and GSK3β phosphorylation, and helped maintain the level of ribosomal RNA necessary for protein production.

The peptide also inhibited the expression of genes related to muscle atrophy, such as MuRF1 and Atrogin-1.

At the same time, he preserved markers of mitochondrial formation and signaling related to AMPK.

The results suggest that MOTS-c may help maintain muscle metabolism, structure, and strength during periods of limited activity. This justifies further research into its potential significance in preventing muscle loss caused by immobilization.

Yuan et al. (2021): MOTS-c and heart function during aerobic training

Yuan and colleagues (2021) investigated the effect of MOTS-c on the heart during aerobic exercise [33].

It is known that physical activity naturally increases the level of MOTS-c, and experimental studies indicate that the peptide itself can improve physical performance.

The researchers therefore examined whether administering MOTS-c during exercise could further improve heart function.

The rats received MOTS-c in conjunction with aerobic training, and the heart rate was assessed using a detailed analysis of the relationship between pressure and volume.

In animals receiving the peptide, an improvement in the mechanical efficiency of the heart muscle was observed. This meant that the heart was more efficient at converting energy into work associated with pumping blood.

The contractile function was also improving, indicating stronger contractions of the heart.

The contraction function also improved, although to a lesser extent.

The results suggest that MOTS-c may enhance beneficial adaptations of the heart to aerobic exercise and act as a mitochondrial signaling molecule related to physical performance.

Che et al. (2019): collagen production in bone cells

Che and colleagues (2019) investigated whether MOTS-c can improve bone health by increasing collagen production in osteogenic cells [34].

Type I collagen is the main structural protein of bone tissue, therefore its production is crucial for bone strength.

Human osteoblasts were exposed to MOTS-c at various concentrations and for different periods of time.

MOTS-c increased cell viability in a concentration-dependent manner and over time of exposure.

The strongest effects were observed at a concentration of 1.0 μM after 24 hours and 0.5 μM after 48 hours.

In addition, MOTS-c increased the expression of genes and proteins associated with type I collagen, including COL1A1 and COL1A2.

At the cellular signaling level, the peptide activated the TGF-β/SMAD pathway, which is involved in the regulation of bone formation.

After the key elements of this route were inhibited, the MOTS-c activity increasing collagen production weakened.

The results suggest that MOTS-c may support bone matrix formation by activating an important pathway responsible for bone formation. However, further research is required to understand its role in bone tissue biology.

Domin et al. (2023): MOTS-c concentration and physical fitness in humans

Domin and colleagues (2023) investigated whether the level of MOTS-c in the blood is related to the physical fitness of healthy adults [35].

The participants performed jumping tests to assess muscle strength and power, as well as an endurance test to determine aerobic capacity.

Higher resting levels of MOTS-c were significantly associated with greater muscle strength, higher jumping power, and greater muscle mass, especially in the lower body.

However, no relationship was found between the level of MOTS-c and the peak oxygen uptake, which is one of the indicators of aerobic capacity.

The results suggest that MOTS-c may be more strongly related to muscle strength and ability to generate power than to overall aerobic performance.

Therefore, MOTS-c can be considered as a potential biomarker of muscle strength rather than general physical endurance.

However, it should be emphasized that the study was observational in nature and did not show that increasing the level of MOTS-c leads to improved muscle strength in humans.

Hu and Chen (2018): differentiation of stem cells into osteoblasts

Hu and Chen (2018) investigated whether MOTS-c can support bone formation by enhancing the differentiation of bone marrow stem cells into osteogenic cells [36].

After administration of MOTS-c, the stem cells showed greater deposition of mineral components, indicating an intensification of bone formation-related activity.

This was confirmed by increased mineralization of calcium deposits and the activity of alkaline phosphatase, which are indicators of the bone-forming process.

In addition, MOTS-c increased the expression of important genes related to bones, such as Runx2, osteocalcin and ALP.

At the molecular level, the peptide activated the TGF-β/Smad pathway.

When the expression of TGF-β1 was suppressed, the MOTS-c-mediated activity supporting bone formation significantly decreased.

The results indicate that MOTS-c can participate in bone regeneration by directing the differentiation of stem cells towards osteogenic cells.

These observations justify further research into its potential significance in osteoporosis and bone tissue repair processes.

MOTS-c as a protective factor in lung damage associated with oxidative stress and inflammation

Experimental studies analyzed MOTS-c as a potential protective factor in lung damage caused by ischemia and reperfusion, inflammation, infections, surgical procedures, and radiation exposure.

In various experimental models, it has been observed that MOTS-c can help maintain the integrity of the pulmonary barrier, limit oxidative stress, and reduce the severity of inflammation and cell death associated with ferroptosis.

Ferroptosis is a form of regulated cell death dependent on iron, which is accompanied by excessive peroxidation of membrane lipids.

One of the main mechanisms analyzed in these studies is the ability of MOTS-c to move into the cell nucleus or activate signaling pathways that protect the cells. These processes can increase the activity of antioxidant mechanisms and support the restoration of energy balance.

In observational clinical studies, the relationships between the concentration of MOTS-c in the blood and the risk of lung damage and the course of recovery were also analyzed.

The results suggest that MOTS-c may be the subject of further research both as a regulator of protective processes and as a potential early biomarker of lung damage. However, this does not mean that its therapeutic efficacy in humans has been confirmed.

Li et al. (2025): MOTS-c and lung damage caused by ischemia and reperfusion

Li and colleagues (2025) investigated how MOTS-c can protect the lungs from ischemic reperfusion injury, which in some cases leads to acute respiratory failure after heart and lung surgeries [37].

Hypoxia occurs when blood flow to tissue is restricted or interrupted. Reperfusion means restoring blood flow, which paradoxically can cause additional damage associated with oxidative stress and inflammation.

In experiments on rats and in cell models, lung damage caused severe oxidative stress and impaired function of the lung barrier.

At the same time, endothelial cells increased the production of their own MOTS-c. This change was associated with better preservation of tissue structure.

Under conditions of oxygen deficiency, followed by reoxygenation, MOTS-c migrated to the cell nucleus via a pathway involving the cytoskeletal protein MYH9.

This process was dependent on signaling induced by oxidative stress and enabled the MOTS-c to interact with nuclear DNA regions that regulate the activity of antioxidant genes.

As a result, the expression of important protective genes such as HMOX1 and NQO1 increased.

HMOX1 encodes heme oxygenase 1, while NQO1 encodes an enzyme involved in oxidative reactions. Both proteins play a role in the cellular response to stress.

The activation of these genes increased the antioxidant capacity of the lung tissue and limited damage.

When MOTS-c was administered externally, the severity of inflammation and oxidative damage was reduced. The pulmonary barrier was better preserved, and the survival of the animals increased.

Researchers also analyzed data from patients undergoing surgeries using extracorporeal circulation.

It was observed that the increase in MOTS-c concentration in the blood within 24 hours after the procedure was strongly associated with a lower risk of acute respiratory failure. This correlation had a higher predictive value than the standard markers analyzed.

The results suggest that MOTS-c can protect the lung tissue by moving into the cell nucleus and strengthening the antioxidant mechanisms.

At the same time, they point to the possibility of further studying the concentration of MOTS-c as an early biomarker of the risk of lung damage.

Zhang et al. (2025): protection of the epithelial barrier in allergic asthma

Zhang and colleagues (2025) analyzed whether MOTS-c can protect the respiratory epithelium in allergic asthma, a disease characterized by chronic inflammation and impaired epithelial barrier function [38].

Patients with asthma had lower concentrations of circulating MOTS-c than healthy individuals.

Next, the researchers used mice exposed to the allergens of house dust mites to recreate selected features of allergic asthma.

Administration of MOTS-c reduced inflammation of the lungs, oxidative stress, and tissue damage.

Importantly, the peptide helped restore the proper level of tight junction proteins that keep epithelial cells close together and limit the penetration of unwanted substances through the respiratory barrier.

An improvement in mitochondrial function was also observed.

In additional experiments, epithelial cell monolayers were used, which were exposed to MOTS-c at a concentration of 10 μM.

Under these conditions, the severity of cell death and oxidative damage decreased significantly.

However, in animals lacking Nrf2, the protective effects of MOTS-c disappeared.

Nrf2 is an important regulator of the antioxidant response that controls the expression of many genes involved in protecting cells from stress.

The results indicate that the activation of Nrf2 is an essential element observed in this model of action of MOTS-c on the epithelial barrier of the respiratory tract.

The study suggests that MOTS-c can protect the respiratory epithelium by enhancing antioxidant defense, limiting cell death, and maintaining proper mitochondrial function and the epithelial barrier.

However, these observations come primarily from experimental models and do not confirm the effectiveness of MOTS-c in the treatment of asthma in humans.

Wang et al. (2025): MOTS-c and remote ischemic conditioning

Wang and colleagues (2025) investigated whether MOTS-c is one of the circulating blood factors responsible for the protective effect of remote ischemic conditioning [39].

Remote ischemic conditioning involves the controlled, short-term restriction and restoration of blood flow in a specific part of the body. This procedure is being studied for the potential to limit organ damage associated with ischemia and reperfusion.

In patients after lung transplantation, the concentration of MOTS-c decreased rapidly after the occurrence of ischemic-reperfusion injury.

However, when non-ischemic conditioning was applied before surgery, the concentration of circulating MOTS-c increased, and the lung damage was less.

Similar results were obtained in mouse models.

Both ischemic conditioning and direct administration of MOTS-c reduced inflammation, leakage of fluid through the walls of blood vessels, and damage to lung tissue.

Importantly, the administration of MOTS-c itself produced the protective effects observed after ischemic conditioning.

In mechanistic studies, it was shown that MOTS-c helped maintain the function of the endothelial barrier by increasing the level of Nrf2.

When Nrf2 was blocked or removed by genetic methods, the protective effect of MOTS-c disappeared.

The results indicate that MOTS-c may be an important signal transmitted through the blood, participating in protective responses induced by ischemic conditioning.

The peptide may help maintain endothelial stability by activating the Nrf2-dependent pathway.

The study provides mechanistic evidence, but it does not mean that administering MOTS-c is a clinically validated method for preventing lung damage after transplantation.

Yin et al. (2020): MOTS-c and acute lung injury caused by bacterial toxins

Yin and colleagues (2020) investigated whether MOTS-c can protect the lungs from acute damage caused by bacterial toxins [40].

In the experiment, mice were given MOTS-c in injections at a dose of 5 mg/kg body weight twice daily for six days before exposure to the toxin.

Earlier administration of the peptide reduced weight loss, pulmonary edema, and the influx of immune cells involved in the inflammatory response.

MOTS-c also reduced the levels of inflammatory mediators such as TNF-α, IL-1β and IL-6.

At the same time, an increase in the levels of factors associated with protective regulation of the immune response was observed, including IL-10, and an increase in the activity of antioxidant enzymes.

At the molecular level, MOTS-c activated AMPK and SIRT1.

AMPK is involved in the regulation of the cellular energy balance, while SIRT1 is an enzyme associated with the stress response, metabolism, and regulation of protein activity.

At the same time, the peptide inhibited MAPK, NF-κB and STAT3 pathways, which may be involved in the development of inflammation and tissue damage.

The results suggest that MOTS-c can limit severe inflammatory lung damage by restoring metabolic balance, reducing oxidative stress, and regulating an excessive immune response.

The doses described in this experiment apply exclusively to the animal model and do not constitute a basis for determining the dosage in humans.

Shen et al. (2025): Lung damage after surgeries with extracorporeal circulation

Shen and colleagues (2025) analyzed whether MOTS-c can protect the lungs from damage occurring after surgeries requiring extracorporeal circulation [41].

In a clinical study involving 107 patients who developed acute lung injury, those with the lowest levels of MOTS-c in the blood had significantly lower levels of MOTS-c.

This observation suggested a relationship between low levels of MOTS-c and greater susceptibility to lung damage.

To better understand the possible mechanisms, the researchers used animal models and cell models of lung damage caused by ischemia and reperfusion.

When MOTS-c was administered before the occurrence of damage, a reduction in structural changes in the lung tissue, inflammation, and oxidative stress was observed.

At the molecular level, MOTS-c helped restore the proper energy metabolism of endothelial cells of the pulmonary vessels by intensifying glycolysis.

Glycolysis is a metabolic process in which glucose undergoes transformations that allow cells to obtain energy.

This effect occurred through the activation of the AMPK–HIF-1α–PFKFB3 pathway.

HIF-1α is a regulator of cell responses to oxygen deprivation, while PFKFB3 participates in the regulation of glycolytic intensity.

Activation of this pathway helped maintain the level of ATP, which is the primary energy carrier in cells, and limited the harmful oxidation of lipids.

As a result, the severity of ferroptosis, a form of cell death that is dependent on iron, decreased significantly.

Importantly, blocking PFKFB3 eliminated the beneficial effects of MOTS-c.

This indicated that restoring proper glycolysis is an essential component of the protective effect of the peptide in the model organism under study.

The results suggest that MOTS-c can protect the lungs from damage associated with heart surgery by improving energy balance and reducing ferroptosis.

Lu et al. (2023): ferroptosis after ischemia and reperfusion of the heart muscle

Lu and colleagues (2023) investigated whether MOTS-c can prevent lung damage associated with ischemia and myocardial reperfusion, which can occur during cardiac surgery [42].

In patients, lower MOTS-c levels after surgery were associated with higher levels of oxidative stress.

In experiments on rats, ischemia and reperfusion caused severe lung damage and strong activation of ferroptosis.

However, when the animals were previously given MOTS-c, the lung damage was significantly less.

An improvement in tissue structure was observed, as was a reduction in oxidative stress and inhibition of the expression of genes related to ferroptosis.

The scientists also conducted experiments on lung epithelial cells that were subjected to oxygen deprivation and then reoxygenation.

Under these conditions, MOTS-c directly limited the death of cells associated with ferroptosis.

The protective action required the activation of the PPARγ pathway.

PPARγ is a nuclear receptor involved in the regulation of lipid metabolism, cell differentiation, and selected inflammatory responses.

When the PPARγ signaling was blocked, MOTS-c stopped showing protective effects.

The results suggest that MOTS-c may limit the lung damage associated with cardiac ischemia by inhibiting ferroptosis through PPARγ activation.

Wen et al. (2024): Protection of the vascular barrier from damage caused by bacterial signals

Wen and colleagues (2024) studied MOTS-c in another model of severe lung injury caused by bacterial peptides that disrupt the function of the blood-vessel barrier [43].

Exposure to the fMLP bacterial signaling molecule resulted in severe inflammation, oxidative stress, ferroptosis, and the breakdown of tight junctions between endothelial cells.

Tight connections help maintain the integrity of the vascular walls and limit uncontrolled fluid infiltration into the surrounding tissues.

The observed damage depended on the activation of the FPR2 receptor and on the disruption of the Nrf2 and MAPK signaling pathways.

FPR2 is a receptor involved in the recognition of certain chemical signals and the regulation of the inflammatory response.

When MOTS-c was administered, many adverse changes were reversed.

Both in mice and in human lung endothelial cells, MOTS-c reduced ferroptosis, reduced the level of inflammatory signals, and helped restore tight junction proteins that prevent fluid leakage.

As a result, the integrity of the blood vessels was better preserved, and the damage to the lungs was less severe.

The results indicate that MOTS-c may be a potential protective factor in experimental models of infection-related lung injury, ferroptosis, and vascular barrier dysfunction.

Zhang et al. (2024): protection of the lungs from radiation-induced damage

Zhang and colleagues (2024) investigated whether MOTS-c can protect the lungs from post-irradiation pneumonia, which is one of the serious possible complications of thoracic radiotherapy [44].

In the mouse experiment, the mice were exposed to a high dose of radiation that included the lungs, and then MOTS-c was administered as injections daily for two weeks.

The radiation caused severe inflammation of the lungs, oxidative stress, mitochondrial damage, and the death of epithelial cells.

However, the administration of MOTS-c significantly reduced tissue damage and lung inflation by inflammatory cells.

The mitochondrial structure of the lung cells was better preserved and the severity of cell death was lower.

In additional cellular experiments, MOTS-c directly protected alveolar epithelial cells against oxidative stress and mitochondrial dysfunction caused by radiation.

At the molecular level, the peptide activated Nrf2 and facilitated its movement into the cell nucleus.

This process strengthened the cellular antioxidant mechanisms.

When Nrf2 was absent, MOTS-c no longer provided protection.

The results suggest that MOTS-c can limit experimental post-injury lung damage by maintaining proper mitochondrial function and activating Nrf2-dependent antioxidant pathways.

However, they do not demonstrate the safety or efficacy of using MOTS-c in patients undergoing radiotherapy.

MOTS-c in pain regulation and inflammation control

Several studies have analyzed MOTS-c as a regulator of processes related to pain and inflammation in models of cancer pain, neuropathic pain, and inflammatory diseases.

Lower levels of endogenous MOTS-c were often associated with increased pain sensitivity, whereas administration of the peptide in experimental models reduced pain-related behaviors.

In some studies, no effects characteristic of opioid painkillers were observed.

At the molecular level, MOTS-c acted on pathways dependent on AMPK, supporting mitochondrial function, limiting excessive activation of immune cells, and reducing inflammatory signaling in tissues of the central and peripheral nervous systems.

At the same time, its effect on protecting cells from oxidative stress and damage associated with metabolic disorders was analyzed.

However, these results primarily concern preclinical studies and do not confirm the analgesic effect of MOTS-c in humans.

Yang et al. (2024): MOTS-c and bone pain associated with cancer

Yang and colleagues (2024) investigated whether MOTS-c can reduce bone pain caused by cancer, which is a serious and often chronic problem associated with bone metastases [45].

In mice with bone pain associated with cancer, the natural level of MOTS-c was significantly lower than in normal conditions.

After administration of MOTS-c in injections, behaviors indicative of pain, including excessive sensitivity to touch, decreased.

However, after AMPK was blocked, the pain-relieving effect disappeared, suggesting that activation of this pathway is essential.

Further analyses revealed two mechanisms of action.

In the spinal cord of MOTS-c, it restored mitochondrial renewal processes, limited the activation of microglia, that is, immune cells involved in pain regulation, and reduced the level of inflammatory signals that increase neuron sensitivity.

At the same time, in the bone marrow environment, MOTS-c limited bone destruction by regulating cells responsible for bone resorption and reducing local inflammatory activity.

Importantly, during the long-term administration in this experiment, no harmful effects on the liver, kidneys, heart, or the lipid parameters analyzed were observed.

The results suggest that MOTS-c can reduce bone pain associated with cancer in animal models by improving mitochondrial function and reducing inflammation through AMPK.

Jiang et al. (2023): neuropathic pain associated with nerve damage

Jiang and colleagues (2023) investigated whether MOTS-c can reduce neuropathic pain caused by nerve damage [46].

In mice with nerve damage, a decreased level of MOTS-c was observed in both blood and spinal cord tissues.

When MOTS-c was administered directly into the spinal cord-associated space, pain sensitivity decreased in a dose-dependent manner.

These effects disappeared after the use of an AMPK inhibitor, but they did not change after blocking the opioid receptors.

This suggested that MOTS-c does not work through the typical opioid pain medication mechanism.

At the molecular level, the peptide activated AMPK in the spinal cord, reduced the activation of microglia, and lowered the level of inflammatory cytokines.

Additionally, it directly protected neurons by reducing oxidative damage and reducing the expression of c-Fos, a marker of neuron activation associated with the processing of pain stimuli.

Compared to morphine, MOTS-c produced fewer adverse effects and showed no signs of tolerance development under the tested conditions.

The results indicate an experimental mechanism of pain regulation in neuropathic pain that is independent of opioid receptors and is associated with AMPK activation.

Jiang et al. (2023): MOTS-c and inflammatory bowel disease

In another study, Jiang and colleagues (2023) analyzed the effect of MOTS-c in an experimental model of inflammatory bowel disease [47].

Administering MOTS-c in injections significantly reduced weight loss, diarrhea, shortening of the large intestine, and tissue damage.

The peptide reduced the levels of inflammatory cytokines, reduced the influx of immune cells, and limited the excessive death of intestinal epithelial cells.

These effects were associated with the regulation of inflammatory signaling mediated by AMPK and stress-activated kinases.

However, administering unmodified MOTS-c orally was ineffective due to its low stability.

To solve this problem, the researchers developed an analog of MOTS-c with increased absorption and activity after oral administration.

The modified peptide significantly alleviated the symptoms of inflammatory bowel disease in the model organism under study.

The results indicate both the potential anti-inflammatory properties of MOTS-c and the importance of stability and the method of delivering peptides in studies of their biological activity.

Shen et al. (2022): Protection of heart cells against oxidative stress

Shen and colleagues (2022) studied heart muscle cells exposed to oxidative and inflammatory stress [48].

When cells were damaged by hydrogen peroxide, previous exposure to MOTS-c improved their survival, reduced the amount of harmful oxidative molecules, and lowered the level of inflammatory cytokines.

MOTS-c reactivated the antioxidant system Nrf2, while simultaneously inhibiting NF-κB signaling, which plays an important role in the development of inflammation.

When the expression of Nrf2 was silenced or the activity of NF-κB was artificially increased, a significant portion of the protective effect of MOTS-c disappeared.

The results suggest that MOTS-c can protect the heart cells by strengthening internal antioxidant mechanisms and limiting inflammatory signaling.

Wang et al. (2024): Central and peripheral mechanisms of pain regulation

Wang and colleagues (2024) analyzed whether MOTS-c can reduce inflammatory pain by simultaneously acting on the central and peripheral nervous system [49].

In several pain models, the administration of MOTS-c significantly reduced pain-related behaviors.

When administered to the central nervous system, the peptide reduced inflammatory cytokine levels in the spinal cord, inhibited the activation of glial cells, and limited excessive stimulation of neurons processing pain signals.

In contrast, local administration reduced inflammation in peripheral tissues and limited the activity of nerve endings responsible for transmitting pain signals.

The results suggest that MOTS-c may influence the transmission of pain information at several levels, from damaged tissue to pain processing centers in the spinal cord.

Yin et al. (2020): MOTS-c and formalin-induced inflammation pain

Yin and colleagues (2020) evaluated MOTS-c in an experimental model of inflammation pain induced by formalin injection [50].

MOTS-c reduced pain behaviors in a dose-dependent manner. Strong effects were observed at a dose of 50 mg/kg body weight.

Blocking AMPK eliminated this effect, indicating a dependence of the effect on this pathway.

The peptide also shifted the immune signaling towards an anti-inflammatory profile and limited the activation of pain-related pathways in the spinal cord.

The results indicate that MOTS-c can reduce inflammatory pain in an animal model by activating AMPK and inhibiting stress-related signaling cascades.

Neuroprotective effect of MOTS-c in oxidative stress, neuroinflammation, and cognitive disorders

Preclinical studies suggest that MOTS-c can protect the brain from oxidative damage, inflammation, and impaired function in various models of neurological stress.

In experimental conditions, MOTS-c helps maintain mitochondrial integrity, activates antioxidant mechanisms, and limits damage to particularly vulnerable populations of neurons, including cells that produce dopamine.

At the same time, improvements in cognitive tests were observed, associated with a reduction in neuroinflammation and the restoration of pathways regulating energy metabolism, which are important for learning and memory.

MOTS-c was also studied for its protection of the blood-brain barrier during severe systemic inflammation, which can lead to secondary damage to the nervous tissue.

Xiao et al. (2023): protection of dopaminergic neurons

Xiao and colleagues (2023) investigated whether MOTS-c can protect dopamine-producing neurons from toxic damage, which is one of the important elements of the pathophysiology of Parkinson's disease [51].

Rentonone, a toxin that disrupts mitochondrial function, was used in cellular and animal models.

Exposure to rotenone caused changes in the level of MOTS-c and the movement of the peptide from the mitochondria into the cell nucleus.

In the core of MOTS-c it directly interacted with Nrf2, an important regulator of the antioxidant response.

This interaction activated protective genes such as HO-1 and NQO1, which are involved in reducing the effects of oxidative stress.

When MOTS-c was administered before exposure to the toxin, the nerve cells showed better mitochondrial function and less oxidative damage.

In rats, the peptide helped maintain markers associated with the dopaminergic system and restored antioxidant signaling impaired by rotenone.

At the same time, the level of Keap1, a protein that limits the activity of Nrf2, decreased.

The results suggest that MOTS-c may enhance antioxidant defense and protect dopaminergic neurons by stabilizing mitochondrial function.

Jiang et al. (2021): memory, learning, and neuroinflammation

Jiang and colleagues (2021) investigated the effect of MOTS-c on learning and memory, particularly under inflammatory or amyloid-related stress conditions [52].

When natural MOTS-c was administered directly to the brain, test results for object recognition and spatial memory improved.

The peptide also reversed memory impairments caused by β-amyloid and inflammation associated with the action of bacterial factors.

These benefits disappeared after AMPK was blocked, indicating the importance of activating this pathway.

In the hippocampus, MOTS-c increased AMPK signaling and reduced astrocyte and microglia activation, which are cells involved in brain inflammatory responses.

As a result, the level of inflammatory cytokines decreased.

Because unmodified MOTS-c does not readily penetrate the brain after systemic administration, scientists developed an analog with enhanced permeability through cell membranes.

The modified peptide reached the brain after oral or intravenous administration and improved memory test scores while reducing neuroinflammation.

The results indicate the possibility of further studying MOTS-c and its analogues in experimental models of inflammatory and amyloid-related memory disorders.

Bai et al. (2025): brain protection during sepsis

Bai and colleagues (2025) investigated whether MOTS-c can protect the brain during sepsis, a life-threatening condition that can cause neurological damage through disruption of the blood-brain barrier [53].

In an experiment, MOTS-c was administered to mice exposed to bacterial toxins at a dose of 20 mg/kg body weight four hours before the damage was caused.

Administration of the peptide significantly improved survival and reduced neurological disorders.

Smaller structural damage and a lower level of inflammatory cytokines were observed in the brain tissue.

Importantly, MOTS-c helped maintain the integrity of the blood-brain barrier.

This was confirmed by reduced permeability of the barrier, less swelling of the brain, and increased expression of proteins responsible for maintaining connections between cells.

Markers of proper blood vessel function and cells supporting the nervous tissue were also restored.

At the same time, astrocyte and microglial activation decreased, and the level of protective growth factors supporting neuron survival increased.

The results suggest that MOTS-c can protect the brain in an experimental model of sepsis by reducing inflammation, strengthening the blood-brain barrier, and supporting regenerative processes.

Figure 3. The role of MOTS-c in pain regulation and tissue protection based on animal studies.

The protective effect of MOTS-c in the liver and its role in cancer research

Several studies have analyzed the various effects of MOTS-c in liver diseases, which include metabolic disorders, viral infections, and stress associated with cancer.

In experimental metabolic models of liver disease, MOTS-c improved mitochondrial function, reduced inflammation and fibrosis, and protected hepatocytes from programmed cell death by stabilizing important proteins responsible for cell survival.

In models of hepatocellular carcinoma, the peptide was studied for its potential to limit the mechanisms of resistance to apoptosis induced by hypoxia.

Its potential role as a biomarker and regulator of antiviral responses in chronic viral hepatitis type B was also analyzed.

Lu et al. (2024): MOTS-c and non-alcoholic fatty liver disease

Lu and colleagues (2024) investigated whether MOTS-c can slow down or reverse nonalcoholic fatty liver disease, referred to as NASH [54].

It is a progressive disease associated with fat accumulation, mitochondrial damage, inflammation, cell death, and fibrosis.

In mice receiving a diet inducing NASH, both prophylactic and subsequent administration of MOTS-c significantly reduced fat deposition in the liver, inflammation, cell death, and fibrosis.

Detailed metabolic studies showed that MOTS-c restored energy production in the mitochondria and corrected metabolic disorders caused by the disease.

An important discovery was the demonstration of the direct binding of MOTS-c to Bcl-2, a protein that protects cells from death.

By stabilizing Bcl-2 and preventing its degradation, MOTS-c protected liver cells from mitochondrial stress and apoptosis.

When Bcl-2 was blocked or silenced, most of the beneficial effects of MOTS-c disappeared.

The results suggest that MOTS-c may slow the development of NASH in an animal model through the stabilization of Bcl-2, the restoration of mitochondrial function, and the reduction of inflammation and fibrosis.

Shen et al. (2025): resistance of liver cancer cells to apoptosis

Shen and colleagues (2025) investigated whether MOTS-c can limit the resistance of liver cancer cells to programmed death under oxygen deprivation conditions [55].

In patients with hepatocellular carcinoma, lower MOTS-c concentrations were found in the blood than in healthy individuals.

In cancer cells grown under hypoxic conditions, the signals responsible for triggering cell death were weakened.

This resulted in resistance to TRAIL-induced apoptosis.

Administration of MOTS-c reversed this resistance by activating AMPK, which restored the activity of MEF2A.

MEF2A is a transcription factor that regulates the expression of the cell death receptors DR4 and DR5.

As a result, the cancer cells became again sensitive to TRAIL and showed a greater intensity of apoptosis.

In mice with MOTS-c tumor lesions, it also limited tumor growth associated with hypoxia.

The results suggest that MOTS-c can restore the sensitivity of cancer cells to apoptosis-inducing signals by reactivating the hypoxia-inhibited pathway.

Lin et al. (2024): MOTS-c in hepatitis B infection

Lin and colleagues (2024) analyzed MOTS-c in HBV infection, focusing both on its potential diagnostic value and antiviral activity [56].

In a large group of patients, the level of MOTS-c was significantly lower in those infected and showed a strong inverse correlation with the amount of virus.

As a potential biomarker of MOTS-c, it showed high accuracy in distinguishing chronic viral hepatitis B from a healthy state.

He also helped distinguish the stages of the disease characterized by an active and an inactive immune response.

In experimental models, MOTS-c reduced virus replication by 50–70%, while improving liver function parameters without detectable toxicity under the tested conditions.

At the molecular level, the peptide increased mitochondrial biogenesis and activated antiviral signaling dependent on MAVS.

An important discovery was the demonstration that MOTS-c regulates mitochondrial remodeling dependent on MYH9 and actin.

This process helped maintain the proper functioning of the mitochondria and supported the antiviral response.

The results indicate that MOTS-c may be a candidate biomarker and a subject of further research into antiviral mechanisms in chronic HBV infection.

General regulatory functions of MOTS-c: resistance, hormones, aging and tissue protection

In subsequent studies, the broad systemic effects of MOTS-c were analyzed, including immune response, neuroendocrine regulation, tissue protection, the aging process, and mechanisms related to the development of tumors.

In various models of disease and stress, MOTS-c influenced the body's resistance by regulating the immune response, maintaining mitochondrial integrity, and stabilizing the activity of genes important for cell survival and regeneration.

The action of MOTS-c in the central nervous system and peripheral tissues may be involved in coordinating energy expenditure, hormonal signaling, reproductive function, and developmental responses to stress.

At the same time, the ability of the peptide to limit degenerative changes in aging tissues and to inhibit tumor growth through interaction with specific proteins was studied.

Zhai et al. (2017): MOTS-c and severe bacterial infection

Zhai and colleagues (2017) investigated whether MOTS-c can improve outcomes in severe bacterial infection [57].

In mice infected with lepo-ornithine Staphylococcus aureus The administration of MOTS-c significantly increased survival and reduced the number of bacteria.

This activity was accompanied by a reduction in the levels of harmful inflammatory cytokines and an increase in the concentration of the anti-inflammatory cytokine IL-10.

MOTS-c also increased the ability of macrophages to destroy bacteria, supporting the elimination of infection by the body.

At the signaling level, the peptide inhibited MAPK activation, which is involved in excessive inflammatory responses, while at the same time increasing the activity of AhR and STAT3.

These pathways may help restore the balance of the immune response.

The results suggest that MOTS-c may increase survival in an experimental model of severe infection by enhancing immune defense and reducing damaging inflammation.

Bahar et al. (2023): regulation of energy metabolism and thyroid hormones

Bahar and colleagues (2023) investigated how MOTS-c affects the central nervous system by regulating energy balance and thyroid function [58].

Mots-c was administered to the rat brains at a concentration of 10 μM or 100 μM.

After administration of the peptide, food intake increased, but body weight remained unchanged.

This suggested a compensatory increase in energy consumption.

MOTS-c significantly reduced the levels of TSH, T3 and T4 in the blood, indicating a suppression of the hypothalamic-pituitary-thyroid axis.

Despite the reduction in the levels of these hormones, MOTS-c increased the expression of UCP1 in adipose tissue and UCP3 in skeletal muscles.

These proteins are involved in mitochondrial heat production and energy dissipation.

The results indicate that MOTS-c administered to the central nervous system can reduce thyroid hormone signaling while increasing mitochondrial thermogenic activity in peripheral tissues.

Waldmann et al. (2023): protection of the auditory cells against gentamicin

Waldmann and colleagues (2023) investigated whether MOTS-c can protect hair cells in the auditory system from damage caused by gentamicin, an antibiotic that can cause permanent hearing loss [59].

The Corti organ preparations were used, containing cells responsible for receiving sound stimuli.

The administration of external MOTS-c significantly increased the survival of epithelial cells after exposure to gentamicin.

At the molecular level, MOTS-c increased phosphorylation of AMPKα, an important component of the pathway responsible for the recognition of the energy state and the resistance of cells to stress.

This mechanism differed from the action of humanin, which acted through AKT signaling.

Maintaining the integrity of the epithelial cells indicated that MOTS-c can increase their resistance to ototoxic stress.

The results support further research on mitochondrial-derived peptides as potential protective factors against drug-induced hearing damage.

Zhong et al. (2022): heart failure caused by chronic pressure overload

Zhong and colleagues (2022) investigated whether MOTS-c can prevent heart failure caused by chronic pressure overload [60].

In mice, a constriction of the cross-sectional part of the aorta was performed to induce pathological myocardial strain.

Then the animals received MOTS-c continuously using subcutaneous osmotic pumps.

Administration of the peptide helped maintain cardiac function, reduced cell remodeling, and limited fibrosis and tissue swelling by inflammatory cells.

The oxidative damage to the heart muscle also decreased significantly.

At the molecular level, MOTS-c activated AMPK signaling.

In cardiomyocyte cultures, the peptide protected against hydrogen peroxide-induced apoptosis through the same pathway.

The results suggest that MOTS-c may limit the development of heart failure caused by pressure overload by reducing oxidative stress, inflammation, and cell death, and maintaining the energy balance of the heart muscle.

Yu et al. (2021): aging of mesenchymal stem cells

Yu and colleagues (2021) investigated the effect of MOTS-c on aging human mesenchymal stem cells derived from the placenta [61].

Administration of MOTS-c restored the cells to morphological characteristics resembling younger cells and improved mitochondrial function and metabolism.

The peptide activated AMPK and inhibited mTORC1 signaling, which often exhibits excessive activity in aging cells.

Mitochondrial respiration and the production of reactive oxygen species decreased, which was interpreted as an improvement in the efficiency of mitochondrial function.

Lipid synthesis was also limited, which corrected another characteristic associated with cellular aging.

Overall, MOTS-c shifted the metabolic profile of aging stem cells towards a state resembling younger cells.

The results suggest that MOTS-c may help restore metabolic and mitochondrial homeostasis in aging human stem cells.

Ozturk et al. (2024): MOTS-c and male reproductive hormones

Ozturk and colleagues (2024) investigated the effect of central administration of MOTS-c on male reproductive hormones under conditions of normal weight and obesity [62].

The mice were administered MOTS-c to the brain cells at a concentration of 10 μM or 100 μM for 14 days.

MOTS-c significantly increased the expression of the GnRH gene and protein in the hypothalamus in both obese and non-obese animals.

Then the increase in testosterone, luteinizing hormone and follicle-stimulating hormone levels in the blood was observed.

This indicated activation of the hypothalamus–pituitary–gonadal axis.

Although the responses were stronger in mice without obesity, a significant increase in hormone levels was also observed in obese animals.

The results suggest that MOTS-c acting in the central nervous system may stimulate the secretion of reproductive hormones even under conditions of endocrine disorders associated with obesity.

Chen et al. (2026): protection of the bearing against oxygen deficiency

Chen and colleagues (2026) investigated whether MOTS-c can protect the placenta from damage caused by oxygen deficiency during pregnancy, which can lead to intrauterine growth restriction of the fetus [63].

Pregnant mice were exposed to hypoxia from the middle to late gestation period. Some of the animals received MOTS-c at a dose of 5 mg/kg body weight.

Hypoxia significantly reduced the level of MOTS-c in the uterus, and lower levels of the peptide were directly associated with smaller fruit masses.

The administration of MOTS-c significantly improved fruit growth and reduced damage to the seed coat.

The formation of blood vessels in the placenta improved, oxidative stress was reduced, and the tissue structure was better preserved.

These benefits disappeared in mice lacking Nrf2, and in endothelial cells subjected to the action of an Nrf2 inhibitor.

This suggested that Nrf2 activation is essential for the observed effect.

The results indicate that MOTS-c can protect the function of the joint during hypoxic stress by activating antioxidant mechanisms and supporting proper blood flow.

The study was conducted on animals and does not constitute a basis for the use of MOTS-c during pregnancy.

Wang et al. (2024): Protection of reproductive functions after exposure to chemotherapy

Wang and colleagues (2024) investigated whether MOTS-c can protect male reproductive functions after exposure to chemotherapy in early life [64].

Cyclophosphamide was administered to female mice before they reached sexual maturity, causing permanent damage to the ovaries and disruption of the development of the sperm cells.

The administration of MOTS-c significantly helped to maintain the structure of the testes and the spermatogenesis process.

The expression of important genes involved in the maintenance of reproductive cells, hormonal regulation, and tissue development shifted towards normal values.

This included the Piwil2, AGT and PTGDS genes, whose activity was impaired by chemotherapy.

The results suggest that MOTS-c may help stabilize mitochondrial function and gene expression during testicular development, supporting the maintenance of reproductive function after exposure to chemotherapy in an animal model.

Li et al. (2019): changes reminiscent of premature aging

Li and colleagues (2019) investigated whether MOTS-c can reverse early aging-like changes caused by long-term exposure of mice to D-galactose [65].

In this model, abnormal accumulation of fat was observed in the liver, visceral adipose tissue, and skin, as well as damage to the intestines and impaired cellular renewal.

In many tissues, there were also abnormalities in the structure and dynamics of the mitochondria.

The administration of MOTS-c significantly reduced abnormal lipid accumulation, restored a more favorable mitochondrial structure, and normalized the activity of genes that control their division and fusion.

In the intestines, the tissue structure improved, cell proliferation increased, and the level of markers of DNA damage associated with aging decreased.

Although changes in body weight and blood glucose levels were small, MOTS-c showed a clear protective effect at the tissue level.

The results suggest that the peptide can limit selected damage associated with accelerated aging in an experimental animal model.

Yin et al. (2024): MOTS-c and the development of ovarian cancer

Yin and colleagues (2024) investigated the role of MOTS-c in the progression of ovarian cancer [66].

In patients with ovarian cancer, significantly lower concentrations of MOTS-c were found in the blood and in the tumor tissue.

Low peptide expression was also associated with a worse quality of life.

In models of cancer cells, MOTS-c significantly limited the growth, migration, and invasion of cells while increasing the severity of programmed cell death and halting the progression of the cell cycle.

At the molecular level, MOTS-c bound to the oncogenic protein LARS1 and promoted its degradation by blocking the stabilizing action of the deubiquitinase USP7.

This led to a reduction in the level of LARS1, a protein involved in processes supporting the growth of tumors.

In mouse models, the administration of MOTS-c significantly reduced tumor size without detectable toxicity under the tested conditions.

The results indicate that MOTS-c can inhibit ovarian cancer growth in experimental models by destabilizing a protein that supports tumor development.

However, they do not provide evidence of the anti-cancer efficacy of MOTS-c in female patients.

Table 1. Summary of the biological functions of MOTS-c in different organs and disease models

Most frequently asked questions about MOTS-c

Is MOTS-c a dietary supplement?

No. MOTS-c is not an approved dietary supplement, nutraceutical, functional food, or vitamin. It is a signaling peptide composed of 16 amino acids, encoded by mitochondrial DNA and naturally produced in the cells of humans and animals. It is formed based on a short open reading frame located in the mitochondrial 12S rRNA gene. Biologically, MOTS-c acts as mitotoxine, a signal of mitochondrial origin that mimics the action of a hormone. It is involved in the regulation of stress responses, energy metabolism, and gene expression, and does not fulfill the function of a nutrient supplied by food.

Products sold online under the name MOTS-c are often labeled as intended solely for scientific research (RUO, for research use only). Such labeling does not confirm the product's safety or suitability for human use. It also does not guarantee the standards appropriate for approved drugs or supplements, including appropriate production conditions, confirmed identity and purity, batch reproducibility, toxicology studies, stability, or long-term safety.

MOTS-c does not have a defined status as an approved ingredient in dietary supplements. The legal classification depends on the jurisdiction. The studies discussed in the article primarily concern an experimental biologically active peptide, not a food ingredient intended for supplementation.

Does MOTS-c apply to burning fat or weight loss?

There is no approved or clinically proven use of MOTS-c for reducing body fat or weight in humans. Interest in this peptide is mainly due to its effects on metabolism, but most of the data comes from studies in animals and laboratory experiments.

In mouse and rat models, MOTS-c influenced lipid metabolism, increased fatty acid oxidation, enhanced thermogenic signaling in adipose tissue, and reduced lipid accumulation in skeletal muscle and the liver. Improved metabolic flexibility was also observed during energy or nutritional stress.

These changes reflect the regulation of metabolism and tissue function, and not the confirmed pharmacological effects of weight loss.

There are no controlled clinical studies showing that the administration of MOTS-c reduces body weight, the amount of adipose tissue, or waist circumference in humans. Also, no clinically significant weight-loss effect has been established, nor has MOTS-c been compared with standard methods of treating obesity. Therefore, online claims regarding weight loss are based primarily on extrapolation from animal studies or anecdotal reports.

What is the recommended dosage of MOTS-c?

There is no approved or recommended dosage of MOTS-c for humans. None of the regulatory authorities mentioned in the article, including the FDA, EMA, and MHRA, have established official dosage guidelines for this peptide.

The doses and concentrations presented in the studies are experimental and relate to specific animal models or cell cultures. In rodents, MOTS-c was often studied at doses of approximately 5–20 mg/kg body weight, depending on the disease model and the duration of the experiment. In in vitro studies, concentrations ranging from nanomolar to micromolar were used.

These values cannot be directly transferred to humans.

No established human pharmacokinetic data are available to determine the absorption, distribution, metabolism, and elimination of MOTS-c. No safe initial dose, maximum tolerated dose, frequency of administration, or duration of therapy have been determined. The dosing protocols published on the internet therefore do not have sufficient clinical validation.

Is there a MOTS-c dosage table?

No. There is no standardized, medically approved, or research-based dosage table for MOTS-c.

The tables available online are unofficial and speculative in nature. They are not based on appropriate pharmacokinetic, toxicological, dose-escalation studies or clinical guidelines for humans.

They often use data derived from animal experiments without adequately considering interspecies differences, safety margins, and regulatory requirements.

The use of such tables for self-administration of the peptide involves an unknown risk, as the safety and efficacy of MOTS-c in humans have not been established.

How is MOTS-c administered in scientific studies?

In most in vivo experiments, MOTS-c was administered by injection, most commonly intraperitoneally (IP) or intravenously (IV).

In studies involving the central nervous system, intrathecal or intradermal administration was also used to ensure direct access of the peptide to the nervous tissue.

Such delivery routes were chosen based on the properties of the peptide, including its susceptibility to degradation in the gastrointestinal tract and the need to control its bioavailability.

Intravenous administration allows researchers to more accurately control the exposure and duration of action, which is not provided by oral administration of unmodified MOTS-c.

The procedures described concern laboratory conditions, not recommendations for use in humans.

Can MOTS-c be taken orally?

Unmodified MOTS-c is characterized by low bioavailability after oral administration and is not considered an appropriate substance for such a method of administration.

Studies indicate that the peptide undergoes rapid enzymatic degradation in the gastrointestinal tract, which limits its absorption into the systemic circulation.

To solve this problem, researchers studied modified MOTS-c analogs, including forms with enhanced penetration through cell membranes and peptide structures that improve stability and uptake by tissues.

However, these solutions remain experimental; they have not been properly tested in humans and are not approved for clinical or consumer use.

Currently, oral administration of MOTS-c is not a method with proven effectiveness.

What is the half-life of MOTS-c?

Available experimental data suggest that MOTS-c may have a relatively short biological half-life.

Animal studies indicate rapid elimination of the peptide, which in some experiments required repeated administration to maintain the observed effects.

Additionally, the natural level of MOTS-c temporarily increases during metabolic stress or physical exertion, and then decreases. This is consistent with the characteristics of a short-acting signaling molecule.

However, the exact half-life of MOTS-c in humans has not been determined because appropriate pharmacokinetic studies have not been conducted.

The duration of action, the speed of elimination, and the exposure profile in humans remain unknown.

Is MOTS-c used in bodybuilding?

MOTS-c is discussed in bodybuilding and athletic circles, mainly in the context of endurance, metabolic performance, and fat metabolism.

However, these discussions are speculative in nature and are based primarily on animal studies or subjective user reports.

MOTS-c is not an approved drug for improving sports performance.

There are no clinical studies in humans confirming that the administration of this peptide increases muscle mass, hypertrophy, maximum strength, or sports performance.

Claims linking MOTS-c with improved athletic performance currently lack sufficient clinical validation.

Does MOTS-c cause side effects?

In animal models, MOTS-c was generally described as being relatively well tolerated.

During short-term experiments, no clear organ toxicity, significant changes in arterial pressure, or repeated adverse changes in markers of liver and kidney function were observed.

However, the lack of adequate safety data in humans is a significant limitation.

There are no long-term safety studies, chronic exposure studies, or adequate assessment of reproductive toxicity, carcinogenic activity, or the interaction of MOTS-c with drugs in humans.

The absence of reported adverse reactions in preclinical studies does not indicate safety for human use. The long-term risk remains unknown.

Is the purchase of MOTS-c legal?

MOTS-c is most often offered as a research peptide, labeled as „not for human use” or „for scientific research only”.

Its legal status depends on the country, the declared purpose of the product and the way it is advertised.

MOTS-c does not have an approved indication as a medicine or dietary supplement intended for human use in the jurisdictions discussed.

The possession of material for research purposes may be legal in certain regions, but the sale or use of MOTS-c for human consumption does not fall within the approved uses.

More information about the distinction between investigational substances and approved medicinal products is presented in the articles. Are peptides legal? and Approved peptide drugs.

How is MOTS-c different from NAD+?

MOTS-c and NAD+ are related to the functioning of mitochondria, but they belong to completely different classes of molecules.

NAD+ is a metabolic coenzyme produced in pathways related to vitamin B3. It directly participates in oxidative reactions and energy transfer processes.

In contrast, MOTS-c is a signaling peptide encoded by mitochondrial DNA.

It acts as a hormone-like mitogen and participates in the regulation of gene expression, stress responses, and metabolic adaptation.

NAD+ precursors are legally offered as dietary supplements in many countries, whereas MOTS-c is not approved for supplementation or medical use.

Their biological functions can complement each other, but they are not mutually interchangeable.

Is MOTS-c approved for medical use?

No. MOTS-c remains the subject of preclinical and translational research.

It has not been approved for the diagnosis, prevention, or treatment of any disease and is not included as a treatment method in clinical practice guidelines.

All the applications discussed have a research nature.

Who should avoid MOTS-c?

Because MOTS-c is an experimental peptide without approved use in humans, it should not be used alone.

The lack of safety data is particularly important for pregnant and breastfeeding women, people with chronic illnesses, and patients taking prescription medications.

Experimental peptides should only be studied under appropriately controlled scientific conditions and not used for self-administration.

Summary

MOTS-c is a mitochondrial-derived peptide composed of 16 amino acids, studied for its role in metabolic signaling, communication between mitochondria and the cell nucleus, stress adaptation, and tissue responses to injury.

The studies discussed in the article cover diabetes, muscle biology, cardiovascular and pulmonary damage, inflammation, neurological models, liver diseases, and other experimental research areas.

In many results, the pathways of AMPK, Nrf2, CK2, and other tissue-specific signaling mechanisms are repeated. However, their significance varies depending on the model and the effect being analyzed.

The key remains the distinction between the biological rationale for the action and clinical evidence.

Many of the effects described come from controlled laboratory experiments or animal models, whereas data on humans are often observational or relate to biomarkers.

These results do not confirm that the administration of MOTS-c produces the same effects in humans.

Questions regarding pharmacokinetics, long-term safety, clinical efficacy, product quality, and the regulatory status of MOTS-c remain unresolved.

Disclaimer

The article is of a scientific and educational nature. It does not constitute medical advice or recommendations for the use of MOTS-c as a standalone supplement for self-administration, supplementation, treatment of diseases, weight loss, or improvement of athletic performance.

Descriptions of experimental methods of administration, doses, and molecular mechanisms serve to faithfully represent scientific research. They are not instructions for the use of MOTS-c in humans.

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58. Bahar, M. R., Tekin, S., Beytur, A., Onalan, E. E., Ozyalin, F., Colak, C., & Sandal, S. (2023). Effects of intracerebroventricular MOTS-c infusion on thyroid hormones and uncoupling proteins. Biology of the Future, 74(1-2), 159-170. https://doi.org/10.1007/s42977-023-00163-6
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66. Yin, Y., Li, Y., Ma, B., Ren, C., Zhao, S., Li, J., Gong, Y., Yang, H., & Li, J. (2024). Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination. Advanced Science, 11(43), e2405620. https://doi.org/10.1002/advs.202405620