Peptide Therapy - MOTS-c

MOTS-c: A Mitochondrial Peptide with Promising Therapeutic Potential

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded within the mitochondrial genome. Since its discovery in 2015, MOTS-c has garnered significant attention for its role in regulating metabolism, enhancing physical performance, and offering potential therapeutic benefits for various age-related and metabolic diseases.

Mechanism of Action

MOTS-c exerts its effects primarily through the activation of the AMP-activated protein kinase (AMPK) pathway, a central regulator of cellular energy homeostasis. By influencing the folate cycle and de novo purine biosynthesis, MOTS-c leads to the accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), which subsequently activates AMPK. This activation enhances glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, thereby improving metabolic efficiency and resilience to stress.

Scientific Research and Benefits

1. Metabolic Health and Insulin Sensitivity

Studies have demonstrated that MOTS-c improves insulin sensitivity, particularly in skeletal muscle, which is crucial for glucose disposal. In mouse models, MOTS-c treatment has been shown to reverse diet-induced obesity and insulin resistance, highlighting its potential in managing type 2 diabetes and metabolic syndrome.

2. Physical Performance Enhancement

MOTS-c levels increase in response to exercise, suggesting its role as an exercise-mimetic. In both young and aged mice, exogenous administration of MOTS-c enhanced physical performance, endurance, and muscle metabolism. These findings indicate its potential in combating age-related decline in physical capacity.

3. Anti-Inflammatory and Cytoprotective Effects

MOTS-c exhibits anti-inflammatory properties by modulating key signaling pathways. It inhibits the MAPK pathway and promotes the expression of anti-inflammatory mediators such as AHR and STAT3. These actions contribute to its protective effects against inflammatory conditions and oxidative stress.

4. Bone Metabolism and Osteoporosis Prevention

Emerging research suggests that MOTS-c plays a role in bone health by promoting osteoblast proliferation and inhibiting osteoclast formation. Through the TGF-β/Smad pathway, MOTS-c enhances bone formation and may serve as a therapeutic agent against osteoporosis, especially in postmenopausal women.

5. Cardiovascular Protection

MOTS-c has been implicated in preventing vascular calcification by activating AMPK signaling and inhibiting the overexpression of receptors associated with cardiovascular diseases. These findings point to its potential in mitigating risks associated with atherosclerosis and related conditions.

Conclusion

MOTS-c stands out as a multifaceted peptide with significant implications for metabolic health, physical performance, and disease prevention. Its ability to mimic exercise-induced benefits, regulate glucose metabolism, and protect against inflammation and bone loss positions it as a promising candidate for therapeutic development. However, further clinical studies are essential to fully understand its efficacy and safety in humans.

References:

1. Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne). 2023 Jan 25;14:1120533. doi: 10.3389/fendo.2023.1120533. PMID: 36761202; PMCID: PMC9905433.
   
2. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016 Nov;100:182-187. doi: 10.1016/j.freeradbiomed.2016.05.015. Epub 2016 May 20. PMID: 27216708; PMCID: PMC5116416.
3. Wan W, Zhang L, Lin Y, Rao X, Wang X, Hua F, Ying J. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023 Jan 20;21(1):36. doi: 10.1186/s12967-023-03885-2. PMID: 36670507; PMCID: PMC9854231.
4. Reynolds, J.C., Lai, R.W., Woodhead, J.S.T. et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 12, 470 (2021). https://doi.org/10.1038/s41467-020-20790-0
5. Changhan Lee, Jennifer Zeng, Brian G. Drew, Tamer Sallam, Alejandro Martin-Montalvo, Junxiang Wan, Su-Jeong Kim, Hemal Mehta, Andrea L. Hevener, Rafael de Cabo, Pinchas Cohen, The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance, Cell Metabolism, Volume 21, Issue 3, 2015, Pages 443-454, ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2015.02.009.
   
6. Yi Xuejie, Hu Guangxuan, Yang Yang, Li Jing, Jin Junjie, Chang Bo. Role of MOTS-c in the regulation of bone metabolism. Frontiers in Physiology, Volume 14 - 2023 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1149120
   
7. Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International Journal of Molecular Sciences. 2022; 23(19):11991. https://doi.org/10.3390/ijms231911991 
8. Reynolds, J.C., Lai, R.W., Woodhead, J.S.T. et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 12, 470 (2021). https://doi.org/10.1038/s41467-020-20790-0