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Mitochondrial ORF of the twelve S c (MOTS-c)
Wednesday, August 14th, 2019

The mitochondria are considered as the “powerhouses of cells”. They are organelles that work like the digestive system which ingests nutrients, breaks them down, and produces fuel or energy for the cells’ biological functions. The mitochondria also pass down information via several signaling molecules in order to enhance communication between each cell. Mitochondrial ORF of the twelve S c (MOTS-c) is one of the mitochondrial-derived peptides (MDPs) that plays an integral role in a wide array of metabolic functions such as glucose metabolism, muscle synthesis, and maintenance of metabolic homeostasis (balance). Interestingly, studies show that MOTS-c holds much potential as a therapeutic option for a multitude of medical conditions because of its unique ability to positively affect various bodily functions.

Overall Health Benefits of Mitochondrial ORF of the twelve S c (MOTS-c)

Proven Health Benefits of MOTS-c

Treats Obesity

Obesity is one of the world’s major health concerns. This debilitating medical condition can dramatically increase one’s risk for heart disease, cancer, stroke, blood vessel problems, and other chronic medical conditions. Numerous studies found that MOTS-c administration can help treat obesity by improving different health parameters and body processes:

  1. MOTS-c may help promote weight loss by reducing the levels of damaging reactive oxygen species during exercise, thereby stimulating physiological adaptation and increased tolerance to exercise. [1-8]
  2. A study found that plasma MOTS-c levels were higher in lean but not in obese individuals. [9]
  3. In rodents, MOTS-c treatment reduced abdominal fat and inhibited adipogenesis (fat cell formation) through down-regulation of multiple genes involved in fat cell development. [10]
  4. In mice fed with a high-fat diet (60% by calories), MOTS-c treatment prevented diet-induced obesity as well as age-dependent and high-fat diet-induced insulin resistance. [11]
  5. In mice, MOTS-c treatment prevented ovariectomy-induced obesity by regulating the production of fat cells. [12]

Improves Exercise Tolerance

MOTS-c can also benefit athletes and physically active individuals. Studies show that this mitochondrial-derived peptide can improve exercise tolerance through various important mechanisms:

  1. MOTS-c stimulates physiological adaptation and increased tolerance to exercise by reducing the levels of damaging reactive oxygen species during exercise, thereby improving performance and results. [13-20]
  2. MOTS-c is actively engaged in transmitting exercise-induced signals to different body organs. [21-26]
  3. MOTS-c improves exercise performance by increasing cellular levels of AICAR and activating AMPK – both of these processes boost energy production. [27-30]

Increases Life Expectancy

Aside from correcting obesity and reducing the risk of various chronic debilitating medical conditions, MOTS-c can also increase life expectancy according to studies:

  1. A Japanese study found that the mitochondrial m.1382A>C polymorphism which occurs within the MOTS-c DNA sequence was associated with exceptional longevity. [31-32]
  2. MOTS-c increases the intracellular levels of NAD+ which is a key metabolic coenzyme involved in oxidation reduction and prevention of age-related diseases. [33-35]

Fights Bone Loss

The age-related decline in bone mineral density causes osteoporosis and fractures. Studies show that MOTS-c can help correct these problems by improving bone quality and preventing bone-damaging processes:

  1. In mice, MOTS-c injection at a dose of 5 mg/kg once a day for 12 weeks alleviated bone loss by inhibiting the process of bone breakdown (osteoclastogenesis). [36]
  2. In rats, MOTS-c treatment improved osteoporosis by boosting the production of bone mesenchymal stem cells (BMSCs), which are cells that can transform into bone-forming cells (osteoblasts). [37]

Fights Bacterial Infection

Sepsis, a condition characterized by the presence of harmful microorganisms in the blood and uncontrolled inflammatory responses, can be a life-threatening condition. Interestingly, a study found that MOTS-c can treat Methicillin-resistant Staphylococcus aureus (MRSA) infection, which is one of the most hard to treat bacterial infections and the major cause of sepsis. [38]

In this study, researchers observed that MOTS-c treatment significantly improved the survival rate and decreased bacteria loads in MRSA-challenged mice. In addition, researchers observed that the treatment significantly reduced the levels of inflammatory substances, suggesting that MOTS-c can be an effective therapeutic option for MRSA infections and other antibiotic-resistant infections.

Improves Blood Sugar Levels

MOTS-c also exerts beneficial effects on blood sugar levels. Studies show that this mitochondrial-derived peptide can help improve the body’s response to insulin hormone:

  1. MOTS-c regulates insulin sensitivity, thereby improving the effects of insulin on the body and reducing blood sugar levels. [39]
  2. MOTS-c balances blood sugar levels by stimulating cellular glucose uptake. [40]
  3. In mice, injection of MOTS-c significantly reduced blood sugar levels and improved the response in glucose tolerance tests (GTT). [41]
  4. In a postmenopausal animal model, MOTS-c treatment reduced weight gain and insulin resistance. [42]

Improves Heart Health

Evidence also suggests that MOTS-c can help preserve heart function by combating the detrimental effects of inflammation on the body and that its levels correlate with cardiovascular health:

  1. In human subjects, lower circulating MOTS-c levels were associated with impaired coronary endothelial function. [43]
  2. In cold-exposed rats, MOTS-c prevented blood vessel dysfunction of the heart. [44]
  3. A study found that MOTS-c may help reduce endothelial dysfunction by suppressing inflammatory pathways such as MAPK/NF-κB. [45]

References:

  1. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182–187. doi:10.1016/j.freeradbiomed.2016.05.015.
  2. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19(5):757–766.
  3. Thevis M, Schanzer W. Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis – Potential implications for sports drug testing programs. Rapid Commun Mass Spectrom. 2016;30(5):635–651.
  4. Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2015
  5. Handschin C. Caloric restriction and exercise “mimetics”: ready for prime time? Pharmacol Res. 2015;103:158–166.
  6. Hunter P. Exercise in a bottle: elucidating how exercise conveys health benefits might lead to new therapeutic options for a range of diseases from cancer to metabolic syndrome. EMBO Rep. 2016.
  7. Li S, Laher I. Exercise pills: at the starting line. Trends PharmacolSci. 2015.
  8. Lee DE, et al. Translational machinery of mitochondrial mRNA is promoted by physical activity in Western diet-induced obese mice. Acta Physiol. 2016.
  9. Cataldo LR, Fernández-verdejo R, Santos JL, Galgani JE. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med. 2018;66(6):1019-1022.
  10. Available from https://www.qscience.com/content/papers/10.5339/qfarc.2016.HBPP1855#abstract_content.
  11. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009
  12. Lu H, Wei M, Zhai Y, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med. 2019;97(4):473-485.
  13. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182–187. doi:10.1016/j.freeradbiomed.2016.05.015.
  14. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19(5):757–766.
  15. Thevis M, Schanzer W. Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis – Potential implications for sports drug testing programs. Rapid Commun Mass Spectrom. 2016;30(5):635–651.
  16. Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2015.
  17. Handschin C. Caloric restriction and exercise “mimetics”: ready for prime time? Pharmacol Res. 2015;103:158–166.
  18. Hunter P. Exercise in a bottle: elucidating how exercise conveys health benefits might lead to new therapeutic options for a range of diseases from cancer to metabolic syndrome. EMBO Rep. 2016.
  19. Li S, Laher I. Exercise pills: at the starting line. Trends PharmacolSci. 2015.
  20. Lee DE, et al. Translational machinery of mitochondrial mRNA is promoted by physical activity in Western diet-induced obese mice. Acta Physiol. 2016.
  21. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454.
  22. Zarse K, Ristow M. A mitochondrially encoded hormone ameliorates obesity and insulin resistance. Cell Metab. 2015;21(3):355–356.
  23. Li S, Laher I. Exercise pills: at the starting line. Trends Pharmacol Sci. 2015;36(12):906–917.
  24. Fuku N, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14(6):921–923.
  25. Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2015.
  26. Handschin C. Caloric restriction and exercise “mimetics”: ready for prime time? Pharmacol Res. 2015;103:158–166.
  27. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454.
  28. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273(6 Pt 1):E1107–E1112.
  29. Narkar VA, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405–415.
  30. Fujii N, et al. Exercise induces isoform-specific increase in 5′AMP-activated protein kinase activity in human skeletal muscle. Biochem Biophys Res Commun. 2000;273(3):1150–1155.
  31. Alexe G, et al. Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet. 2007;121(3–4):347–356.
  32. Fuku N. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015.
  33. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464–471.
  34. Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208–1213.
  35. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217.
  36. [1] Ming W, Lu G, Xin S, et al. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochem Biophys Res Commun. 2016;476(4):412-419.
  37. Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018;22(21):7156-7163.
  38. Zhai D, Ye Z, Jiang Y, et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Mol Immunol. 2017;92:151-160.
  39. Lee C, Zeng J, Drew BG, Sallam T, Martin‐Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P (2015) The mitochondrial‐derived peptide MOTS‐c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21, 443–454.
  40. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182–187. doi:10.1016/j.freeradbiomed.2016.05.015.
  41. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-54.
  42. Kim SJ, Miller B, Kumagai H, Yen K, Cohen P. MOTS-c: an equal opportunity insulin sensitizer. J Mol Med. 2019;97(4):487-490.
  43. Qin Q, Delrio S, Wan J, et al. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. International journal of cardiology. 2018; 254:23-27.
  44. Available from https://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.1015.2.
  45. Li H, Ren K, Jiang T, Zhao GJ. MOTS-c attenuates endothelial dysfunction via suppressing the MAPK/NF-κB pathway. Int J Cardiol. 2018;268:40.
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