MOTS-c 40mg

MOTS-c Peptide

MOTS-c (Mitochondrial Open reading frame of the 12S rRNA-c) is a 16–amino acid peptide encoded by the mitochondrial genome (within the 12S rRNA region). It is classified among mitochondrial‑derived peptides (MDPs) that may act as retrograde signals between mitochondria and nucleus, modulating metabolism and stress responses. Under metabolic stress (e.g. glucose restriction, oxidative stress), MOTS‑c has been shown to translocate from mitochondria into the nucleus, where it can influence nuclear gene expression and metabolic pathways.

Overview & Mechanism of Action

MOTS‑c enhances insulin sensitivity and glucose metabolism, especially in skeletal muscle, partly via activation of AMPK and interactions with one‑carbon metabolism / AICAR pathways. In mice fed a high‑fat diet, MOTS‑c treatment prevented obesity, improved glucose tolerance, reduced insulin resistance, and increased energy expenditure.

In aged and middle‑aged mice, MOTS‑c administration improved treadmill endurance, grip strength, gait, and metabolic parameters compared to controls. MOTS‑c reduces high‑fat diet–induced muscle atrophy signaling by downregulating expression of myostatin and modulating pathways (CK2‑PTEN‑mTORC2‑AKT‑FOXO1). It has also been shown in animal models to suppress MAPK (ERK, JNK, p38) phosphorylation and reduce pro‑inflammatory cytokine production in septic or inflammatory conditions.

Emerging evidence suggests MOTS‑c promotes osteoblast proliferation, differentiation, and mineralization, while inhibiting osteoclastogenesis (bone resorption) via AMPK and TGF‑β / Smad signaling pathways.

Chemical Characteristics

Short peptide (≈ 16 AA) encoded in mitochondrial DNA as part of 12S rRNA sORF. Under stress, the peptide relocalizes to the nucleus in an AMPK‑dependent manner. Expression levels vary by tissue (muscle, plasma) and decline with age.

Research and Clinical Insights

Plasma MOTS‑c levels decline with age, while skeletal muscle expression increases in older men. MOTS‑c levels correlate with insulin resistance metrics in humans, especially among lean individuals. A review of MOTS‑c in diabetes and aging highlights its therapeutic potential in type 1 & type 2 diabetes.

In ovarian cancer, MOTS‑c expression is decreased in tumor tissue and serum, and exogenous MOTS‑c suppressed proliferation, migration, and invasion of cancer cells via interaction with LARS1 and modulation of ubiquitination. Also, MOTS‑c mRNA and protein abnormalities have been observed in adrenal tumors, correlating with metabolic markers.

MOTS‑c improves mitochondrial homeostasis, reduces ROS, and restores youthful phenotypes in aged human placenta‑derived mesenchymal stem cells (hPD‑MSCs) by activating AMPK and inhibiting mTORC1.

Strengths & Future Directions

Strengths:• Multi-system effects: metabolism, muscle, inflammation, bone• Endogenous origin (mitochondrial) gives the peptide unique regulatory potential• Stress‑responsive nuclear translocation suggests dynamic regulation

MOTS-c — References

• Lee, C., Zeng, J., Drew, B. G., Sallam, T., Martin-Montalvo, A., Wan, J., Kim, S. J., Mehta, H., Hevener, A. L., de Cabo, R., Cohen, P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443–454.https://doi.org/10.1016/j.cmet.2015.02.009
• Zhang, X., Zhai, M., Zhang, H., Zhang, Y., Jia, J., Sun, Y., Xu, W., Wu, H., Zheng, J. MOTS-c alleviates oxidative stress and apoptosis in H9c2 cardiomyoblasts induced by hypoxia/reoxygenation through the AMPK pathway. Peptides. 2021;135:170428.https://doi.org/10.1016/j.peptides.2020.170428
• Lu, H., Tang, S., Xue, L., Li, N., Liu, Y., Sun, J., Xu, J. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Aging (Albany NY). 2019;11(14): 5205–5216.https://doi.org/10.18632/aging.102102
• Reza, M. M., Subramaniyam, N., Sim, C. M., Ge, X., Sathiakumar, D., McFarlane, C., Sharma, M., Kambadur, R. Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nature Communications. 2017;8(1):1104.(Note: This study discusses MOTS-c alongside exercise-induced peptides in skeletal muscle pathways.)https://doi.org/10.1038/s41467-017-01131-0
• Reyes, M., Sifuentes-Franco, S., Sandoval-Garcia, F., Quiroz, A., Briones-Herrera, A., Jaramillo-Rangel, G., Ramos, M. A. The MOTS-c peptide regulates muscle mitochondrial homeostasis through AMPK activation in aged mice. GeroScience. 2022;44(5):2227–2242.https://doi.org/10.1007/s11357-022-00576-4
• Shen, W., Wang, L., Li, X., et al. MOTS-c improves insulin sensitivity to regulate glucose metabolism via the AMPK pathway in skeletal muscle of mice. International Journal of Obesity. 2021;45:2490–2501.https://doi.org/10.1038/s41366-021-00895-2
• Qin, Q., Delrio, S., Wan, J., Xiong, S., Liu, J., Zhang, P., Lee, C. Mitochondrial-derived peptide MOTS-c prevents diet-induced obesity by increasing energy expenditure and improving insulin sensitivity. FASEB Journal. 2018;32(10):5093–5103.https://doi.org/10.1096/fj.201800089R
• Du, C., Fang, M., Li, Y., Li, L., Wang, S., Li, J., Liu, X., Xu, Y., Hou, J. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatric Diabetes. 2018;19(6):1077–1084.https://doi.org/10.1111/pedi.12671
• Kim, K. H., Lee, C. Mitochondrial-derived peptides: update on bioactivities and future directions. Current Opinion in Endocrinology, Diabetes and Obesity. 2021;28(2):133–141.https://doi.org/10.1097/MED.0000000000000621

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