MOTS-C Peptide (20MG)

This 2015 paper in Cell Metabolism (Lee et al.) identified MOTS-c and characterized its activity in cultured cells and in mice. In the main animal experiment, male mice fed a 60% high-fat diet received daily MOTS-c doses for 8 weeks. Treated mice gained less body weight than vehicle-treated mice on the same diet, while food and caloric intake were the same in both groups.

The authors also reported changes in blood glucose and insulin, skeletal-muscle insulin signaling, liver fat on histology, and whole-body energy expenditure. They linked these changes to a folate–AICAR–AMPK pathway, measured mainly in skeletal muscle.

Scope: All in vivo data in this paper come from mice, and the mechanistic work comes from cultured rat cell lines. The study did not test MOTS-c in people.

• Citation: Lee C, Zeng J, Drew BG, et al. Cell Metabolism. 2015;21(3):443–454.
• Study type: Discovery and mechanism study (cell culture plus mouse experiments)
• Animals: Male CD-1 and C57BL/6 mice, including young, middle-aged and aged groups
• Main model: 60% high-fat diet versus matched control diet for 8 weeks
• Administration in the study: Intraperitoneal, in mice
• Main measurements: Body weight, food intake, glucose and insulin, glucose tolerance, hyperinsulinemic-euglycemic clamp, indirect calorimetry, liver histology, AMPK and GLUT4 in muscle
• Disclosure: Two authors reported stockholder and consultant roles with CohBar, Inc.

Mitochondria are usually described as the cell's energy producers. Researchers have become increasingly interested in their role as signaling hubs. Before this paper, humanin was the only known peptide encoded by a short open reading frame in mitochondrial DNA. Lee and colleagues searched for additional mitochondrial-encoded peptides and identified MOTS-c within the 12S rRNA gene.

In this study, MOTS-c levels in skeletal muscle and blood were lower in aged mice (32 months) than in young mice (4 months). The researchers then asked whether giving MOTS-c would change glucose handling and body weight in mouse models of aging and high-fat feeding.

The paper combined several experiments. Each used its own animals, duration and protocol:

• High-fat diet study: 8-week-old male CD-1 mice received a 60% high-fat diet or a matched control diet (n = 10 per group), with daily intraperitoneal MOTS-c (0.5 mg/kg/day) or vehicle for 8 weeks. Researchers tracked body weight, food and caloric intake, glucose, insulin, liver histology, and muscle AMPK and GLUT4.
• Energy expenditure: A separate group of high-fat-fed CD-1 mice was treated for 3 weeks and then measured by indirect calorimetry (respiratory exchange ratio, heat production and activity).
• Insulin sensitivity: High-fat-fed C57BL/6 mice were treated for 7 days at a higher experimental dose (5 mg/kg/day) and then studied with a hyperinsulinemic-euglycemic clamp.
• Aging comparison: Young (3 months) and middle-aged (12 months) male C57BL/6 mice were treated for 7 days. Insulin-stimulated glucose uptake was then measured in isolated soleus muscle.
• Cell studies: HEK293 cells and rat L6 muscle cells were used to map the metabolic pathway.

Doses are reported here only to describe the published methods accurately. They are specific to these mouse protocols.

On the control diet, MOTS-c treatment did not change body weight. On the 60% high-fat diet, MOTS-c-treated mice gained less weight over 8 weeks than vehicle-treated mice, and the authors reported identical caloric intake between groups. The authors reported a similar result in C57BL/6 mice.

In the 3-week calorimetry experiment, treated mice had a higher respiratory exchange ratio, which indicates a greater share of carbohydrate in fuel use. They also produced more body heat, while total physical activity was similar between groups. The authors concluded that the body-weight difference was associated with higher energy expenditure rather than lower food intake.

At the end of the 8-week high-fat diet study, MOTS-c-treated mice had lower circulating insulin than high-fat-fed controls. The authors described this as preventing diet-induced hyperinsulinemia.

In the 7-day clamp study, the glucose infusion rate needed to hold blood glucose steady was about 30% higher in treated mice. Insulin-stimulated glucose disposal, which mainly reflects skeletal muscle, also increased. Hepatic glucose production was similar between groups. The authors interpreted this pattern as an effect concentrated in skeletal muscle rather than the liver.

In the aging comparison, isolated muscle from 12-month-old mice took up less glucose in response to insulin than muscle from 3-month-old mice. After 7 days of MOTS-c treatment, muscle from the older mice took up glucose at levels comparable to the younger group.

Liver sections stained with hematoxylin and eosin (H&E) showed less lipid accumulation in high-fat-fed mice treated with MOTS-c than in high-fat-fed controls. This was a histological observation in mice at the end of the 8-week protocol. The study did not measure liver function or longer-term outcomes.

In cultured cells, MOTS-c acted on the folate cycle and slowed de novo purine synthesis. This raised levels of AICAR, an intermediate of that pathway that is also a known activator of AMP-activated protein kinase (AMPK). Cells exposed to MOTS-c took up more glucose. Adding folic acid reversed the effect, which supports a folate-cycle link.

In high-fat-fed mice, MOTS-c treatment was associated with increased AMPK phosphorylation and higher GLUT4 levels in skeletal muscle. Together with the clamp results, the authors proposed skeletal muscle as a major target tissue. They described AICAR–AMPK as partly, but not fully, explaining the effects they observed.

• The in vivo experiments used small groups of mice (about 6–10 per group), mostly males, over periods of 7 days to 8 weeks.
• The paper combines several different protocols, doses and mouse strains. Each finding applies to its own experiment.
• Results in mouse diet models and cell lines do not establish effects, safety or appropriate exposure in any other species.
• MOTS-c research has grown since 2015, including studies of exercise and endogenous MOTS-c levels. Those studies fall outside this paper and are not summarized here.

Lee et al. (2015) identified MOTS-c as a peptide encoded in mitochondrial DNA. In mice fed a high-fat diet, daily MOTS-c administration was associated with less weight gain at equal caloric intake, higher energy expenditure, lower insulin levels and less liver lipid on histology. Clamp and isolated-muscle studies pointed to skeletal muscle as the main site of action, through a folate–AICAR–AMPK pathway.

These are findings from mouse and cell-culture experiments only. This summary is provided for research and educational purposes. Statements on this page have not been evaluated by the FDA. Research compounds offered on this site are for laboratory research use only. They are not intended for human or veterinary use, or to diagnose, treat, cure, mitigate or prevent any disease.