MOTS-c Peptide and Potential Effects on Insulin & Inflammation

by | Feb 7, 2023 | Research


Peptides consist of chains of amino acids that play a crucial role in many biological processes. One such peptide, MOTS-c (mitochondrial ORF of the 12S rRNA type-c), has recently emerged as a potential key player in maintaining good health. MOTS-c is naturally produced in the human body, is found in mitochondria, and is considered the powerhouse of the cell.

This peptide is encoded in the mitochondrial genome and appears to be able to regulate nuclear gene expression in the mitochondria in response to various factors, such as metabolic stress. Laboratory experiments suggest that it may have anti-aging, anti-inflammatory and metabolic benefits. However, the true potential of MOTS-c has yet to be thoroughly studied, and further research is needed to determine the whole spectrum of its effects.

This article will discuss the latest scientific studies on MOTS-c and examine the potential benefits of this peptide with regard to muscle function, insulin resistance, inflammation, bone health, and metabolic and heart health.


MOTS-c Peptide Overview

MOTS-c is a peptide that is naturally produced in the human body. It is a component of mitochondria, the cellular organelles responsible for producing energy. The structure of the peptide consists of 16 amino acids and bears the sequence H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH.

Preliminary research investigates its potential for managing age-related diseases, including diabetes, cardiovascular diseases, osteoporosis, postmenopausal obesity, and Alzheimer’s disease.[1] The studies report, “Under stress conditions, MOTS-c translocates to the nucleus where it regulates a wide range of genes in response to metabolic dysfunction.” Thus, MOTS-c is thought to regulate energy metabolism and may have anti-inflammatory and anti-aging effects. 


MOTS-c Peptide Research in Insulin Resistance, Metabolism, and Muscle

One of the most actively researched potential benefits of MOTS-c is its effects on insulin resistance and metabolic health. Several animal studies suggest MOTS-c may help improve glucose metabolism in metabolic disorders such as insulin resistance by targeting skeletal muscles.[2] This mechanism of action may work by enhancing glucose uptake by skeletal muscles and also helps decrease levels of visceral fat.

One of these studies reports that MOTS-c targets the skeletal muscle and inhibits the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK pathway activation.[3] As a result, MOTS-c treatment in mice appeared to prevent age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity.

MOTS-c may also help improve metabolic health by stimulating the “browning” of white (beige) fat and increasing thermogenesis in fat tissue.[4] These effects of MOTS-c are believed to be mediated by the activation of the ERK signaling pathway. 

MOTS-c has also shown promise in studies on managing gestational diabetes, a type of diabetes that occurs due to increased insulin resistance in pregnancy.[5] In a GDM mouse model, daily administration of MOTS-c during pregnancy appeared to significantly reduce hyperglycemia, improve insulin sensitivity and glucose tolerance, and reduce birth weight and risk of offspring death. 

The benefits of MOTS-c on skeletal muscles do not appear to be limited to improving their glucose uptake. Animal research also suggests that the peptide has the potential to impact muscle atrophy in obesity and type 2 diabetes.[6] MOTS-c appears to function by decreasing myostatin levels in plasma in mice and elevating AKT phosphorylation, which inhibits the activity of FOXO1, a transcription factor for muscle-wasting genes. It may also effectively reduce dystrophic muscle atrophy, specifically in Duchenne Muscular Dystrophy (DMD) models.[7] 


MOTS-c Peptide Research in Heart Health

MOTS-c peptides may have a protective effect on the heart muscle due to improved mitochondria function in the myocytes. According to one study in a murine model of heart failure, the peptide appeared to reduce the inflammation response and improve cardiac function.[8] The peptide also appeared to activate the AMPK pathway, reduce cell apoptosis, and improve the antioxidant capacity in the heart of the mice.

MOTS-c may also help reduce the adverse effects of type 2 diabetes on the heart, as studies in diabetic rats reported that peptide administration appeared to result in improved myocardial mitochondrial damage, preserved cardiac systolic and diastolic function, and altered 47 disease-causing genes related to apoptosis, immunoregulation, angiogenesis, and fatty acid metabolism.[9]

Thanks to the activation of the AMPK and the anti-oxidative effects of the peptide, animal studies also suggest it may help reduce inflammation in the heart and protect against vascular calcification (VC), which is a complication of atherosclerosis.[10][11]

Researchers report that MOTS-c may also improve mechanical heart efficiency, enhance heart systolic function, and show a tendency to improve diastolic function in healthy mice.[12] These results suggest that MOTS-c could help to optimize the cardiovascular benefits of athletic training. Scientists also suggest that MOTS-c may have heart function benefits similar to exercise via activating the NRG1-ErbB4-C/EBPβ pathway.[13] 


MOTS-c Peptide and Bone Health

By activating the phosphorylated AMPK, MOTS-c may provide benefits for bone health. One study reports that in a murine model of osteoporosis, MOTS-c treatment appeared to significantly inhibit osteoclast differentiation and reduce bone loss, as determined by micro-CT examination.[14] The scientists concluded that “MOTS-c may exert as an inhibitor of osteoporosis via AMPK dependent inhibition of osteoclastogenesis.

Another animal trial reported reduced bone erosion and inflammation in a model of osteolysis induced by ultra-high molecular weight polyethylene particles.[15] MOTS-c appeared to increase the osteoprotegerin ratio to receptor activator of nuclear factor kappa-B ligand in osteocytes, inhibiting osteoclastogenesis.

Some laboratory experiments suggest that MOTS-c may promote bone fracture healing by inducing bone marrow stem cell (BMSCs) differentiation into osteoblasts.[16] This is achieved by increasing the relative levels of bone markers (ALP, Bglap, and Runx2) and activating the TGF-β pathway by the FOXF1 protein to ultimately stimulate the mineralization ability in BMSCs. 



Recent research on the MOTS-c peptide has provided exciting new insights into its potential to benefit human health. From its proposed anti-aging effects to its potential as a treatment for obesity and related metabolic disorders, MOTS-c shows promise as a versatile and practical peptide. While more research is needed to fully understand the mechanisms by which MOTS-c confers these benefits and to determine the safety and efficacy of MOTS-c for human use, the early results are very promising.

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