MOTS-c is a peptide hormone encoded in the mitochondrial genome. It regulates metabolic homeostasis and enhances physical performance. It is a mitochondria-derived peptide (MDP) that promotes biosynthesis of the endogenous AMP analog AICAR and consequently AMP-activated protein kinase (AMPK). Induces cellular and systemic glucose uptake and improves insulin sensitivity. Shown to prevent diet-induced obesity (DIO) in mice. Potential anti-obesity and anti-aging compound.
MOTS-c, as a mitochondrial coding regulator, has endocrine-like and nuclear transcriptional regulation on muscle metabolism, insulin sensitivity and body weight. Approximately 11.9-fold increase in endogenous MOTS-c levels has been found in skeletal muscle following exercise (compared to pre-exercise values), and this increase can remain for 4 hours following exercise. In addition, circulating endogenous MOTS-c levels increase 1.6-fold during exercise, 1.5-fold after exercise, and then return to baseline levels after 4 hours. MOTS-c, as a new type of mitochondrial signal molecule, may stimulate exercise-mediated physiological responses to increase endurance. Therefore, MOTS-c can be used as a motion simulator to mediate the function of the motion signal system.
MOTS-c has also been found to be involved in the regulation of nuclear gene expression by binding to transcription factors. Under resting conditions, MOTS-c is mainly distributed in the mitochondria outside the nucleus. When metabolic stress occurs, MOTS-c in cells can be transferred to the nucleus in an AMPK-dependent manner and bind to transcription factors regulated by ARE, thus improving the stress resistance of cells.
Furthermore, MOTS-c plays the role of endocrine-like factors by regulating nuclear transcription to restore homeostasis. The function may have important implications for age-related diseases in response to metabolic stress by promoting intracellular homeostasis, and MOTS-c gene polymorphisms are associated with human lifespan. Moreover, MOTS-c may improve diabetes by inhibiting insulin resistance and diet-induced obesity. MOTS-c can promote glucose utilization, inhibit oxidative stress, activate NF-κB to inhibit inflammation, and effectively protect coronary artery endothelial cell dysfunction[3].
MOTS-c targets skeletal muscle and can enhance glucose metabolism. Therefore, MOTS-c plays an important role in the regulation of cardiovascular, diabetes, exercise and longevity. It is a new mitochondrial signaling mechanism and plays a role in regulating intracellular and intercellular metabolism. This substance could triggers the activation of AMPK and accumulation of 5-aminomidazole-4-carboxamide ribonucleotide (AICAR), a known AMPK activator, by inhibiting the folate cycle and de novo purine biosynthesis[1-2].
MOTS-c is reported to be safe in recommended dosages. The side effects of this compound include Injection site pruritus. As with all injections, redness and pain at the injection site may be present. As MOTS-c targets the folate cycle and de novo purine biosynthesis pathways, a depletion of intracellular 5-methyl tetrahydrofolate (5-MTHF) may occur when using MOTS-c protocols.
[1] Mohtashami Z, et al. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Mohtashami, 2022; 23: 11991.
[2] Zheng Y, et al. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology, 2023; 14: 1120533.
[3] Yuejun Zheng, Tianhui Wang, Zilin Wei. “MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation.” Frontiers in Endocrinology 14 (2023): 1120533.
