Since its initial discovery, Vilon has been the subject of numerous studies and clinical trials in Russia and other countries. Its potential effect may include interacting with genes, cell proliferation, immune system functioning, coagulation, aging, organ function, and even cancer cells.

Vilon is arguably the shortest peptide to have any biological activity and is made of two amino acids, lysine, and glutamate. This has led to the peptide being recognized as Lysylglutamic acid or Lysylglutamate. Vilon has a chemical formula of C11H21N3O5 and a molecular weight of 275.30 g/mol. The amino acid L-lysine is a positively charged amino acid, while L-glutamate is a negatively charged amino acid. This gives Vilon (Lysylglutamate) an overall neutral charge.

Overall, the structure of Vilon is relatively simple compared to larger peptides and proteins. Still, its unique composition and chemical properties make it an interesting molecule for further study and potential therapeutic development.

Research Studies on the Vilon Peptide

Vilon Peptide and Cell Proliferation, Gene Expression

Studies suggest that Vilon may affect gene expression and, more specifically, programmed cell death (apoptosis). One laboratory experiment reported that the peptide reduced the apoptotic death of spleen lymphocytes in rats caused by irradiation.^[1] 

Another study examined the effect of Vilon on cell proliferation in spleen organotypic tissue cultures of rats of different ages (3 days, 3 weeks, and 2 years old). The results suggested that Vilon could stimulate cell proliferation in both young and old rats.^[2]

The peptide may achieve this effect by interacting directly with certain genes. Experiments reveal that Vilon may have the ability to modify the chromatin structure of lymphocytes in elderly individuals (aged 75-88 years).^[3] This may lead to the release and activation of genes that are otherwise repressed due to aging, and what’s more, may indicate the potential anti-aging properties of Vilon.

Vilon Peptide and Aging

Animal studies reported that administering Vilon (Lys-Glu) to female CBA mice from the 6th month of life might enact physical activity, endurance, and prolonged lifespan while preventing spontaneous neoplasms.^[4] According to the study, the administration of Vilon did not appear to affect the estrous function or free radical processes. The long-term use of Vilon did not appear to cause any negative effects on animal development either, indicating that it may be safe for geroprotection and preventing age-related diseases.

Several in vitro studies also report that the peptide may activate regeneration mechanisms in explanted cells in young and aged rats.^[5][6] The peptide was reportedly effective, even in ultrasmall doses. The researchers noted that “the stronger effect on the explants taken from the old rats suggests that Vilon is a candidate for geriatric research and practice.”

Another study suggested that low-dose ionizing radiation appeared to cause accelerated aging in the thymus and spleen of rats; 7 however, treatment with Vilon appeared to partially inhibit this process and furthermore provided anti-aging benefits. 

Vilon Peptide and the Immune System

Experiments in murine models of immunosuppression report that Vilon may have immunomodulating effects. One animal study examined the effect of Vilon administration in rats exposed to mercury and gamma radiation, which are known to suppress the immune system. The exposure caused lymphopenia and DNA damage, but administration of the Vilon peptide appeared to normalize the lymphocyte count and reduce the morbidity of rats over a period of 15 months after exposure.^[8] 

In another trial, Vilon was suggested by researchers to increase the expression of lymphocyte differentiation marker CD5 in thymic cells. It appeared to induce T-cells precursor differentiation towards CD4+ T-helpers.^[9] CD4+ T-helper cells are a type of white blood cell that plays a crucial role in the immune response by activating and coordinating the activity of other immune cells. Vilon was suggested to stimulate the expression of argyrophilic proteins in nucleolar organizer regions of thymocytes and epithelial cells and promote thymocyte transformation into proliferating blast cells.^[10] 

Vilon Peptide and Coagulation

The possible effect of the peptide on coagulation is one of the rare effects studied in humans. One study reported that Vilon administration appeared to significantly reduce or eliminate accelerated blood coagulability, decrease levels of natural anti-coagulants, and increase fibrinogen and fibrin complexes in patients with type 1 diabetes.^[11] This conclusion was reported despite the effect being less pronounced in elderly patients with severe forms of the disease.

Another trial in elderly patients with type 1 diabetes reported that adding Vilon to the complex therapy appeared to increase natural anticoagulant content, stimulate fibrinolysis, and reduce insulin dosage.^[12] Vilon purportedly did so by stabilizing the immune system by normalizing active T-lymphocytes, B-lymphocytes, and IgA while reducing T-helpers’ content, T-dependent, and non-T-dependent NK cells. The researchers also reported that “in most cases, Vilon reduced the dose of insulin necessary for the stabilization of carbohydrate metabolism.”

Vilon Peptide and Cancer

Vilon was developed as an immunomodulator and has also been studied clinically in treating elderly cancer patients with stage III rectal and colon cancer.^[13] Researchers suggested it could improve the 2-year survival rate, prevent post-operative and remote complications, recurrences, and tumor dissemination, as well as improve patients’ quality of life. However, it is important to note that these findings are based on preliminary results and require further investigation. Other than this clinical trial, Vilon has been studied primarily in mice.

According to one murine model of bladder cancer, treatment with the Vilon peptide appeared to reduce the incidence of preneoplastic and early neoplastic changes in urinary bladder mucosa and significantly inhibited carcinogenesis.^[14] The incidence of urinary bladder tumors was also reportedly lower in Vilon-treated animals than controls. However, some studies show conflicting results. One animal experiment reports that Vilon treatment appeared to increase the incidence of mammary cancer and shorten the time for tumor development in female transgenic mice.^[15] 

Conclusion

Vilon is a synthetically developed peptide comprised of two amino acids with strong immunomodulatory properties. It has been studied extensively since its development and has been suggested to host numerous potential therapeutic properties. While much is still unknown about the mechanisms of action and potential benefits of Vilon, its development represents an important milestone in the search for new tools that interact with immunity, gene expression, and aging.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Khavinson VK, Kvetnoii IM. Peptide bioregulators inhibit apoptosis. Bull Exp Biol Med. 2000;130(12):1175-1176.
2. Bykov NM, Chalisova NI, Zeziulin PN. Retsiproknye sootnosheniia proliferativenoĭ aktivnosti v tsentral’noĭ i perifericheskoĭ zonakh organotipicheskoĭ kul’tury selezenki pri deĭstvii vilona u krys raznogo vozrasta [Reciprocal relation of proliferative activity in central and peripheral zones of splenic organ culture exposed to vilon in rats of various ages]. Adv Gerontol. 2003;11:104-108.
3. Lezhava T, Monaselidze J, Kadotani T, Dvalishvili N, Buadze T. Anti-aging peptide bioregulators induce reactivation of chromatin. Georgian Med News. 2006;(133):111-115.
4. Khavinson VK, Anisimov VN, Zavarzina NY, et al. Effect of vilon on biological age and lifespan in mice. Bull Exp Biol Med. 2000;130(7):687-690. doi:10.1007/BF02682106
5. Kniaz’kin IV, Iuzhakov VV, Chalisova NI, Grigor’ev EI. Funktsional’naia morfologiia organotipicheskoĭ kul’tury selezenkoi krys razlichnogo vozrasta pri deĭstvii vilona [Functional morphology of organotypic culture of spleens from rats of various ages exposed to vilon]. Adv Gerontol. 2002;9:110-115.
6. Bykov NM, Chalisova NI. Osobennosti deĭstviia ul’tramalykh doz vilona v organotipicheskoĭ kul’ture selezenki krys raznogo vozrasta [Characteristics of effect of ultralow doses of vilon in organotypic culture of spleens from rats of various ages]. Adv Gerontol. 2002;10:85-87.
7. Kniaz’kin IV, Poliakova VO. Deĭstvie vilona na timus i selezenku v radiatsionnoĭ modeli prezhdevremennogo stareniia [The effect of vilon on the thymus and spleen in a radiation model of premature aging]. Adv Gerontol. 2002;9:105-109.
8. Ivanov SD, Khavinson VKh, Malinin VV, et al. Adv Gerontol. 2005;16:88-91.
9. Sevostianova NN, Linkova NS, Polyakova VO, et al. Immunomodulating effects of Vilon and its analogue in the culture of human and animal thymus cells. Bull Exp Biol Med. 2013;154(4):562-565. doi:10.1007/s10517-013-2000-0
10. Raikhlin NT, Bukaeva IA, Smirnova EA, et al. Expression of argyrophilic proteins in the nucleolar organizer regions of human thymocytes and thymic epitheliocytes under conditions of coculturing with vilon and epithalon peptides. Bull Exp Biol Med. 2004;137(6):588-591. doi:10.1023/b:bebm.0000042720.40439.16
11. Kuznik BI, Kolesnichenko LR, Kliuchereva NN, Pinelis IuI, Ryzhak GA, Khamaeva TsB. Adv Gerontol. 2006;19:107-115.
12. Kuznik BI, Isakova NV, Kliuchereva NN, Maleeva NV, Pinelis IS. Adv Gerontol. 2007;20(2):106-115.
13. Ias’kevich LS, Krutilina NI, Kostetskaia TV, Ryzhak GA, Khavinson VKh. Adv Gerontol. 2005;16:97-100.
14. Pliss GB, Mel’nikov AS, Malinin VV, Khavinson VK. Inhibitory effect of peptide vilon on the development of induced rat urinary bladder tumors in rats. Bull Exp Biol Med. 2001;131(6):558-560. doi:10.1023/a:1012354603132
15. Anisimov VN, Khavinson VK, Provinciali M, et al. Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int J Cancer. 2002;101(1):7-10. doi:10.1002/ijc.10570

Liraglutide peptide was first developed in the 1990s, with the intention for use in combination with diet and exercise to improve blood sugar control in adults with type 2 diabetes. The development of Liraglutide was based on the discovery of the hormone glucagon-like peptide-1 (GLP-1), which is involved in regulating blood sugar levels in the body. It has been widely researched since its development, with some studies outlined below.

Liraglutide Peptide and Body Composition

Liraglutide peptide may have significant potential for weight loss, even in individuals who do not have type 2 diabetes. One study focused on obese and overweight participants who lost at least 5% of their initial weight during a low-calorie diet run-in.^[1] The participants were randomly assigned to receive either Liraglutide peptide treatments or a placebo for 56 weeks, which appeared to lead to an additional 6 kg of weight loss on average for the study period. Liraglutide peptide also appeared to produce small improvements in some cardiovascular risk factors. The scientists reported that “From randomization to week 56, weight decreased an additional mean 6.2%  […] with liraglutide and 0.2% […] with placebo.”

Another 56-week-long study of 846 patients reported similar results, with an average of 5-6% of observed weight loss in most participants.^[2]

Researchers also suggested that combining Liraglutide peptide and exercise may lead to twice the weight loss compared to exercise alone.^[3] One of the longest studies to investigate the effect of Liraglutide peptide on weight loss was a 20-week randomized, double-blind, placebo-controlled trial with a 2-year extension involving 564 overweight adults.^[4] Participants received either once-daily administration of Liraglutide peptide, a placebo, or an open-label weight loss medication in addition to diet and exercise counseling. The study’s results suggested that Liraglutide peptide recipients lost more weight than those on a placebo or medication. Moreover, participants on Liraglutide also appeared to experience improvements in metabolic syndrome and blood pressure.

Liraglutide Peptide and the Endocrine System

Liraglutide peptide has some potential to act as an incretin in the endocrine system, specifically in the pancreas, which enhances insulin secretion. The peptide was developed to mimic the action of the incretin hormone GLP-1, which stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner.^[5] The effect appears to depend on the serum glucose levels, diminishing if the glucose is low and thereby preventing the occurrence of hypoglycemia.

When Liraglutide peptide is administered to people with type 2 diabetes, research studies suggest it may enhance the incretin effect by increasing GLP-1 levels in the bloodstream. This leads to increased insulin secretion and decreased glucagon secretion, resulting in improved blood sugar control. These studies reported apparently significant improvements in various parameters related to blood sugar control in patients with type 2 diabetes.^[6] These included improved levels of glycated hemoglobin, body mass index (BMI), cardiovascular parameters, etc., all within the 3-6 months of the study. The scientists reported that the “meaningful difference in weight, body mass index, glycated hemoglobin (HbA1C), systolic blood pressure, and diastolic blood pressure from baseline to follow-up was -5.36 kg, -2.14 kg/m2, -1.76%, -12.38 mmHg, and 5.55 mmHg, respectively.” In addition, experiments observed that Liraglutide might also exhibit a protective effect on the function of the pancreas in type 2 diabetes patients and preserve the function of the beta cells, which normally produce insulin.^[7]

Liraglutide Peptide and the Digestive System

Liraglutide peptide may slow down the emptying of food from the stomach into the small intestine, leading to a feeling of fullness and reduced appetite. Research studies suggest that 1-h gastric emptying was, on average, 23% lower in studies than placebo therapy, although that performance was dose-dependent.^[8] Scientists observed that the speed of gastric emptying eventually returned to normal after 4 hours.

This proposed effect of Liraglutide peptide on slowing down gastric emptying may help in weight management and may also improve blood sugar control in people with diabetes. This is due primarily to slow stomach emptying, which naturally prolongs the feeling of fullness and helps reduce appetite. Furthermore, gastric emptying slows down the release of blood sugar after a meal, which helps improve glycemic control in diabetes patients.

Liraglutide Peptide and the Nervous System

Apart from slowing down gastric emptying, Liraglutide peptide has also been suggested by researchers to have the ability to suppress appetite by directly affecting the brain and its perception of hunger. This potential effect could be due to the peptide’s interaction with GLP-1 receptors in the brain, whose activation would lead to reduced appetite.^[9] Liraglutide peptide has shown promise as a neuroprotective peptide in murine models of Parkinson’s Disease (PD)^[10] with scientists suggesting that the peptide could reduce neuroinflammation and reduce neuron loss.

PD is a neurodegenerative disorder that affects the nervous system, particularly the dopaminergic neurons in the brain. While the exact cause of PD is unknown, some evidence suggests that an autoimmune reaction that destroys these neurons may contribute to the development of the disease. Liraglutide peptide is currently under active investigation in a phase II trial in PD patients (clinical trial identifier NCT02953665).

Conclusion

Liraglutide peptide has been widely researched for its potential to treat type 2 diabetes, obesity, and other conditions. However, ongoing research is also exploring the potential of Liraglutide in other areas. It has demonstrated great potential in research applications.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study [published correction appears in Int J Obes (Lond). 2013 Nov;37(11):1514] [published correction appears in Int J Obes (Lond). 2015 Jan;39(1):187]. Int J Obes (Lond). 2013;37(11):1443-1451. doi:10.1038/ijo.2013.120
2. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial [published correction appears in JAMA. 2016 Jan 5;315(1):90]. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676
3. Lundgren JR, Janus C, Jensen SBK, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021;384(18):1719-1730. doi:10.1056/NEJMoa2028198
4. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide [published correction appears in Int J Obes (Lond). 2012 Jun;36(6):890] [published correction appears in Int J Obes (Lond). 2013 Feb;37(2):322]. Int J Obes (Lond). 2012;36(6):843-854. doi:10.1038/ijo.2011.158
5. Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2009;43(9):1433-1444. doi:10.1345/aph.1M134
6. Zameer R, Kamin M, Raja U, et al. Effectiveness, Safety, and Patient Satisfaction of Liraglutide in Type 2 Diabetic Patients. Cureus. 2020;12(8):e9937. Published 2020 Aug 22. doi:10.7759/cureus.9937
7. Kapodistria K, Tsilibary EP, Kotsopoulou E, Moustardas P, Kitsiou P. Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic β-cell apoptosis. J Cell Mol Med. 2018;22(6):2970-2980. doi:10.1111/jcmm.13259
8. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784-793. doi:10.1038/ijo.2013.162
9. Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15(3):181-187. doi:10.1007/s11154-014-9289-5
10. Cao B, Zhang Y, Chen J, Wu P, Dong Y, Wang Y. Neuroprotective effects of liraglutide against inflammation through the AMPK/NF-κB pathway in a mouse model of Parkinson’s disease. Metab Brain Dis. 2022;37(2):451-462. doi:10.1007/s11011-021-00879-1

Overview of Modified GRF (1-29)

Modified GRF (1-29) is a modified version of GRF (1-29), the smallest amino-acid sequence from the original GHRH that may still retain the ability to trigger the receptors in the pituitary gland and induce an HGH spike. As the name suggests, GRF (1-29) and modified GRF (1-29) are made of 29 amino acids. However, Modified GRF (1-29) has 4 of the original 29 amino acids replaced with the intention to make the peptide more resistant to rapid cleavage by the enzyme dipeptidyl peptidase-4. This cleavage was previously reported to result in peptide inactivation.^[1] More specifically, the replaced amino acids are the 2nd, 8th, 15th, and 27th amino acids.

Due to this replacement, the peptide is also known as tetrasubstituted GRF (1-29), and its sequence is Tyr-D-Ala-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg. As a result, the half-life of the peptide has been anticipated to last from 10 – 30 mins.  One of the main modifications is the replacement of L-alanine with D-alanine in the 2nd spot.^[2] According to the researchers, “the disappearance half-time of the D-Ala2 analog was 6.7 +/- 0.5, whereas that of GHRH-(1-29)-NH2 was 4.3 +/- 1.4 min (P < 0.05). These findings demonstrate that the D-Ala2 substitution contributes to the enhancement of biological activity by reducing metabolic clearance.“

Research

Mod GRF (1-29) was developed to have a longer half-life but retain identical effects to GRF (1-29), also known as Sermorelin. Since no studies investigate the effects of modified GRF (1-29) without DAC, the following reports will be based on GRF (1-29) research.

Mod GRF (1-29) and HGH Synthesis & Growth

Researchers have reported GRF (1-29) to have the potential to increase HGH pulse synthesis.^[3] Repeated dosing may lead to a significant increase in growth hormone levels. The increase in peak HGH levels can lead to various benefits, such as increased growth in children and improved muscle mass, fat loss, physical performance, and energy levels in adults. Research studies have been conducted on children with growth failure, and the administration of the peptide appeared to yield promising results universally. However, further research is needed to confirm the peptide’s overall and long-term effects.

Mod GRF (1-29) and Body Composition

One study focused on the effects of GRF (1-29) administration reported the peptide’s apparent ability to increase growth velocity by 74%, maintained for up to a year of therapy. These findings suggest that GRF (1-29) therapy may be a viable treatment option for children with GHD experiencing growth failure.^[4] A trial conducted in adult males reported that administering GRF (1-29) for a duration of 4 months resulted in a significant increase in lean body mass by 1.26 kg. However, it is important to note that such effects were only observed in male subjects and were not observed in females.^[5] This could be attributed to the fact that GRF (1-29) therapy may not cause human growth hormone (HGH) peaks to exceed the physiological limits, which may differ between genders due to biological variations. For example, as the growth hormone remains within its physiological limits in women, it is still significantly impacted by the negative effect of estrogens on IGF-1 production, the main anabolic mediator of HGH.^[6] Researchers reported that estrogen affects the HGH-IGF-1 axis “by decreasing liver secretion of insulin-like growth factor-I (IGF-I).“

GRF (1-29) may also cause fat loss, especially around the abdomen, due to its potential HGH-boosting effects. A study involving 19 participants across different age groups found that 2 weeks of GRF (1-29) therapy could improve their waist-to-hip circumference ratio.^[7]

Mod GRF (1-29) and HGH-Related Benefits

A study investigating the effects of GRF (1-29) in older adults found that it might lead to significant improvements in strength and endurance levels.^[8] This trial involved 11 participants, who exhibited an increased capacity for performing crunches and improved shoulder pressing strength after receiving GRF (1-29) therapy. These findings suggest that GRF (1-29) may be a promising therapy for improving physical function in older adults. 

Age-related changes in muscle mass and strength may also result in decreased mobility and quality of life, and interventions such as GRF (1-29) therapy may potentially mitigate these negative effects. Further research is needed to explore the potential benefits and limitations of GRF (1-29) therapy for improving physical performance.

Another HGH-related benefit may be the promotion of skin cell growth and increased collagen deposition within the derma. A study on elderly men and women revealed that a 4-month treatment course of GRF (1-29) administrations appeared to increase skin thickness significantly.^[9] This finding suggests that GRF (1-29) may play a role in improving skin quality and reducing signs of aging, such as fine lines and wrinkles. Further research is needed to fully understand the effects of GRF (1-29) on skin health. Still, these initial findings are promising for individuals seeking to improve their skin’s appearance and overall health. 

Conclusion

In conclusion, Modified GRF (1-29), also known as tetrasubstituted GRF (1-29), is a synthetic analog of growth hormone-releasing hormone designed to stimulate the release of growth hormone in the body.  The modifications in its amino acid sequence may make it more resistant to rapid cleavage by enzymes and increase its half-life, leading to potential therapeutic uses in various conditions, such as growth hormone deficiency, osteoporosis, and muscle wasting. 

Studies in the unmodified GRF (1-29) show that it may increase HGH synthesis and growth, improve body composition, and have other HGH-related benefits, such as improving physical function in older adults.  However, further research is needed to confirm these findings, especially if they also apply to the effects of Modified GRF (1-29) without DAC. 

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Scarborough R, Gulyas J, Schally AV, Reeves JJ. Analogs of growth hormone-releasing hormone induce release of growth hormone in the bovine. J Anim Sci. 1988 Jun;66(6):1386-92. doi: 10.2527/jas1988.6661386x. PMID: 3135287.
2. Soule S, King JA, Millar RP. Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men. J Clin Endocrinol Metab. 1994 Oct;79(4):1208-11. doi: 10.1210/jcem.79.4.7962295. PMID: 7962295.
3. Achermann JC, Hindmarsh PC, Robinson IC, Matthews DR, Brook CG. The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2) and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation: studies in normal and post cranial irradiated individuals. Clin Endocrinol (Oxf). 1999 Nov;51(5):575-85. doi: 10.1046/j.1365-2265.1999.00839.x. PMID: 10594518.
4. Thorner M, Rochiccioli P, Colle M, Lanes R, Grunt J, Galazka A, Landy H, Eengrand P, Shah S. Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. Geref International Study Group. J Clin Endocrinol Metab. 1996 Mar;81(3):1189-96. doi: 10.1210/jcem.81.3.8772599. PMID: 8772599.
5. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.
6. Cook DM. Growth hormone and estrogen: a clinician’s approach. J Pediatr Endocrinol Metab. 2004 Sep;17 Suppl 4:1273-6. PMID: 15506073.
7. Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab. 1992 Aug;75(2):530-5. doi: 10.1210/jcem.75.2.1379256. PMID: 1379256.
8. Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart KJ, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RG. Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men. Metabolism. 1997 Jan;46(1):89-96. doi: 10.1016/s0026-0495(97)90174-8. PMID: 9005976.
9. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.

ARA-290 peptide is a promising molecule that has recently gained attention. This small, synthetic peptide is a derivative of erythropoietin (EPO), a hormone that stimulates the production of red blood cells. However, unlike EPO, ARA-290 does not appear to affect erythropoiesis and has been suggested to have potent tissue-protective effects.

In this article, we will explore what ARA-290 peptide is, how it works, and its potential applications.

ARA-290 Peptide Overview

ARA-290 is a synthetic peptide first developed by a research team led by Dr. Schmidt at the New York University School of Medicine. The team discovered the innate repair receptor and found that activating it with a synthetic peptide could improve tissue repair and reduce inflammation in various preclinical disease models.
After further testing and refinement, they developed ARA-290 peptide as a potential agent for various conditions involving tissue damage, inflammation, and neuropathic pain. It consists of 11 amino acids designed to mimic a specific sequence of erythropoietin. The amino acid sequence of ARA-290 peptide is Tyr-Glu-Pro-Pro-Pro-Tyr-Gly-Gly-Lys-Pro-Ala
This sequence was identified as the “receptor-specific” site of erythropoietin (EPO), which interacts with a specific receptor on the surface of cells to elicit tissue-protective effects. ARA-290 was developed to specifically target this receptor and avoid interactions with the EPO receptor, which is responsible for the hormone’s effects on erythropoiesis. 

ARA-290 Studies on Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

Sarcoidosis-associated small nerve fiber loss and damage (SNFLD) refers to a condition in which the small nerve fibers in the peripheral nervous system are damaged or lost due to sarcoidosis. These are the fibers responsible for transmitting sensory information, such as pain, temperature, and touch. Sarcoidosis is a systemic autoimmune inflammatory disease that can affect multiple organs in the body, including the nerves. It leads to the formation of tiny clusters of inflammatory cells called granulomas, which can cause tissue damage and organ dysfunction.
ARA-290 peptide was hypothesized to effectively reduce symptoms in neuropathy models, which led to investigating its potential for managing neuropathy due to Sarcoidosis-associated SNFLD.^[1] According to the research, these supposed benefits are likely due to the anti-inflammatory effects of the peptide that it exerts in nervous tissues. The scientists concluded that “ARA290 dose-dependently reduced allodynia coupled to suppression of the spinal microglia response, suggestive of a mechanistic link between ARA290-induced suppression of central inflammation and relief of neuropathic pain symptoms.”
Clinical studies in patients with sarcoidosis also support this hypothesis, suggesting that ARA-290 peptide may effectively reduce neuropathy symptoms by ameliorating the sarcoidosis-associated SNFLD. One trial with 38 patients reported that 28 days of daily administration of ARA-290 peptide appeared to lead to significantly improved neuropathic symptoms, a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test.^[2]
Another 28-day trial in 64 patients reports that taking doses ARA-290 peptide may significantly improve pain severity and functional capacity in treated individuals.^[3] The results of this and other trials suggest that ARA-290 has a disease-modifying effect on small nerve fiber loss in patients with sarcoidosis.^[4] 

ARA-290 Peptide and Management of Diabetes and Related Complications

Insulin resistance plays a significant role in the development and progression of type 2 diabetes. Preliminary research on the glycemic and metabolic effects of ARA-290 peptide was conducted in mice suffering from insulin resistance, hyperlipidemia, hepatic lipid accumulation, and impaired insulin signaling pathways in skeletal muscle.^[5] A high-fat, high-sucrose diet-induced the condition, and therapy with ARA-290 peptide appeared to reduce hepatic lipid deposition and normalized serum glucose and lipid profiles. In this murine mode, the treatment appeared to improve insulin sensitivity and glucose uptake in skeletal muscle, attenuate the overproduction of myokines, and enhance mitochondrial biogenesis in skeletal muscle. Many other animal studies also report that ARA-290 may significantly improve glycemic control and lower insulin resistance in rats with type 2 diabetes.^[6]
Clinical studies also report similar results in humans with diabetes. According to one trial in 9 patients with diabetes (mainly type 2 diabetes) and diabetic macular edema (DME), 12 weeks of ARA-290 peptide therapy appeared to lead to improvements in central subfield retinal thickness, tear production, diabetic control, and albuminuria.^[7]
Another trial included 24 subjects with type 2 diabetes who received ARA-290 peptide or a placebo for 28 days and were followed for an additional month.^[8] The researchers reported no safety issues, and those receiving ARA-290 appeared to exhibit an improvement in HbA1c and lipid profiles. They noted that “subjects receiving ARA 290 exhibited an improvement in hemoglobin A1c (Hb A1c) and lipid profiles throughout the 56 [day] observation period.” Neuropathic symptoms and mean corneal nerve fiber density also appeared to improve in the ARA-290 group, suggesting that it may benefit both metabolic control and neuropathy in subjects with type 2 diabetes. 

ARA-290 Peptide and Anti-inflammatory, Anti-Aging Effects

Studies have suggested that ARA-290 peptide may reduce inflammation by modulating the activity of the innate immune system, which is responsible for the initial response to infections and tissue damage. Specifically, ARA-290 peptide has been suggested to inhibit the activation of macrophages and reduce the production of pro-inflammatory cytokines, such as TNF-alpha and IL-1beta, in models of colon inflammation.^[9]
One trial in aged rats reports that chronic ARA-290 peptide treatment may reduce inflammation and fibrosis in the heart, improve mitochondrial and myocardial cell health, and preserve left ventricular ejection fraction.^[10] ARA-290 also apparently mitigated the age-associated increase in blood pressure, preserved body weight, and reduced markers of organism-wide frailty.
Thus, preliminary research suggests that ARA-290 peptide may have potent anti-aging and anti-inflammatory effects. The benefits of the peptide for patients with type 2 diabetes and sarcoidosis may also be partially related to its potent anti-inflammatory effects. 

Conclusion

More research is needed to fully understand ARA-290’s potential.  Currently, the peptide has research-only status, and it is not intended for managing or treating any condition. 

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Swartjes M, van Velzen M, Niesters M, Aarts L, Brines M, Dunne A, Cerami A, Dahan A. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain. 2014 Feb 16;10:13. doi: 10.1186/1744-8069-10-13. PMID: 24529189; PMCID: PMC3928087.
2. Dahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, van Velzen M, Sarton E, Niesters M, Tannemaat MR, Cerami A, Brines M. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med. 2013 Nov 8;19(1):334-45. doi: 10.2119/molmed.2013.00122. Erratum in: Mol Med. 2016 Oct 20;22:674. PMID: 24136731; PMCID: PMC3883966.
3. Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts LPHJ, Tavee J, Tannemaat MR, Dunne AN, Kirk RI, Petropoulos IN, Cerami A, Malik RA, Brines M. Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Invest Ophthalmol Vis Sci. 2017 May 1;58(6):BIO52-BIO60. doi: 10.1167/iovs.16-21291. PMID: 28475703.
4. Heij L, Niesters M, Swartjes M, Hoitsma E, Drent M, Dunne A, Grutters JC, Vogels O, Brines M, Cerami A, Dahan A. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med. 2012 Nov 15;18(1):1430-6. doi: 10.2119/molmed.2012.00332. PMID: 23168581; PMCID: PMC3563705.
5. Collino M, Benetti E, Rogazzo M, Chiazza F, Mastrocola R, Nigro D, Cutrin JC, Aragno M, Fantozzi R, Minetto MA, Thiemermann C. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br J Pharmacol. 2014 Dec;171(24):5802-15. doi: 10.1111/bph.12888. Epub 2014 Nov 24. PMID: 25164531; PMCID: PMC4290718.
6. Muller C, Yassin K, Li LS, Palmblad M, Efendic S, Berggren PO, Cerami A, Brines M, Östenson CG. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med. 2016 May;21(1):969-978. doi: 10.2119/molmed.2015.00267. Epub 2015 Dec 29. PMID: 26736179; PMCID: PMC4818260.
7. Lois N, Gardner E, McFarland M, Armstrong D, McNally C, Lavery NJ, Campbell C, Kirk RI, Bajorunas D, Dunne A, Cerami A, Brines M. A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema. J Clin Med. 2020 Jul 14;9(7):2225. doi: 10.3390/jcm9072225. PMID: 32674280; PMCID: PMC7408632.
8. Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015 Mar 13;20(1):658-66. doi: 10.2119/molmed.2014.00215. PMID: 25387363; PMCID: PMC4365069.
9. Nairz M, Haschka D, Dichtl S, Sonnweber T, Schroll A, Aßhoff M, Mindur JE, Moser PL, Wolf D, Swirski FK, Theurl I, Cerami A, Brines M, Weiss G. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep. 2017 Oct 12;7(1):13012. doi: 10.1038/s41598-017-13046-3. PMID: 29026145; PMCID: PMC5638901.
10. Winicki NM, Nanavati AP, Morrell CH, Moen JM, Axsom JE, Krawczyk M, Petrashevskaya NN, Beyman MG, Ramirez C, Alfaras I, Mitchell SJ, Juhaszova M, Riordon DR, Wang M, Zhang J, Cerami A, Brines M, Sollott SJ, de Cabo R, Lakatta EG. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med. 2023 Jan 18;9:1096887. doi: 10.3389/fcvm.2022.1096887. PMID: 36741836; PMCID: PMC9889362.

Sermorelin Acetate, a synthetic peptide, was developed to function as an analog of a naturally occurring hormone called growth hormone-releasing hormone (GHRH). While GHRH has 44 amino acids, Sermorelin peptide is truncated down to 29 amino acids. Sermorelin peptide is also known as the Growth Hormone Releasing Factor (1-29) or GRF (1-29). Sermorelin is the smallest fragment of the GHRH chain that appears to possess the same functions, namely, stimulating the pulsatile release of human growth hormone (HGH) by the pituitary gland. Due to this potential, Sermorelin peptide has been classified by researchers as a Growth Hormone Secretagogue (GHS). Like GHRH and other GHSs, Sermorelin may increase the production of HGH in the pituitary gland, resulting in higher and more frequent peaks of the growth hormones. This would also result in elevated levels of Insulin Growth Factor-1 (IGF-1), the primary anabolic mediator of the effects of HGH in the human body.

What is the Sermorelin?

Sermorelin was first synthesized in the early 1980s and has been avidly researched since its development. Scientists posit that it has the potential to be used as a provocation test for the diagnosis of pituitary disorders and, more specifically, growth hormone deficiency (GHD). The peptide may also hold potential therapy for growth failure in children. It is made of 29 amino acids and bears the sequence YADAXFXNSYRKVLGQLSARKLLQDXMSR. Sermorelin peptide, aka GRF (1-29), should not be confused with Modified GRF (1-29), which has 4 of the original 29 amino acids replaced with the intent to increase its half-life from 10 to 30 minutes. 

General Research in Sermorelin

Sermorelin Peptide and Endocrine Effects

As a GHRH analog, Sermorelin peptide has been researched primarily for its potential to stimulate pulsatile HGH synthesis via the pituitary gland. Studies observed that as long as the pituitary gland is functioning correctly, Sermorelin, combined with the amino acid Arginine, may induce a significant spike in serum HGH levels.^[1] The researchers also noted that “doses of Sermorelin are well tolerated. Transient facial flushing and pain at the [administration] site were the most commonly reported adverse events.” 

HGH is the primary hormone that regulates growth in children. Clinical trials with growth failure also report that Sermorelin peptide appeared to effectively increase growth velocity with growth failure and functional pituitary glands by 74%.^[2] Further research reported that 6 months of either taking Sermorelin peptide or HGH therapy, appeared to exhibit a similar increase in growth velocity.^[3] Studies also reported an apparent significant increase in serum HGH levels after several days of Sermorelin peptide administration.^[4]

The peptide may also affect the levels of other hormones apart from HGH, such as insulin and sex hormones.  Although high HGH is often associated with increased insulin levels and insulin resistance, one 16-week trial suggested that Sermorelin may improve insulin sensitivity in males but not in females.^[5] The trial participants receiving Sermorelin peptide appeared to have slightly lower glucose levels, potentially due to the increase in IGF-1 and its insulin-like effects. One animal trial also reported an increase in gonadotropic hormones and testosterone levels in male mice, but there is no clinical research to support these findings.^[6] 

Sermorelin Studies in Strength, Endurance, and Cardiovascular Health

Sermorelin may benefit strength, endurance, body composition, and cardiovascular health thanks to its apparent HGH-stimulating effects. In one trial with 9 male participants, researchers reported that 4 months of Sermorelin peptide administration appeared to increase lean body mass by 1.26 kg.^[7] The study also included 10 women, but they were not reported to experience any changes in body composition. The researchers concluded, “These observations suggest that GHRH analog administration induced anabolic effects favoring men more than women. Further studies are needed to define the gender differences observed in response to GHRH analog administration.”

Results from another trial in 11 older adults suggested that Sermorelin peptide appeared to improve their strength and endurance levels significantly.^[8] The participants could perform more crunches and became stronger at shoulder pressing. One study of 19 young and old participants also showed that as little as 2 weeks of Sermorelin peptide therapy appeared to improve the ratio of their waist to hip circumferences.^[9] The waist-hip ratio is an essential indicator of various metabolic and cardiovascular risks. An improved waist-hip ratio may improve various cardiometabolic parameters such as blood pressure.^[10] In fact, in one study of 11 male participants, Sermorelin peptide appeared to be capable of lowering the systolic blood pressure from 135 to 125 mmHg on average. 

Sermorelin Peptide and Skin

Scientists posit that Sermorelin has the potential to function in increasing HGH levels. From this assumption, it may be possible for Sermorelin peptide to increase the proliferation of new skin cells, ultimately leading to increased collagen deposition inside the derma. 

One trial in older men and women reported that 4 months of Sermorelin peptide administration appeared to significantly increase their skin thickness.^[11] Additionally, the men, but not the women, also experienced improved libido. Increasing collagen production in the skin may help combat signs of skin aging, such as reduced skin thickness and elasticity. 

Sermorelin Peptide and the Nervous System

One trial in 23 young individuals suggested that even a one-time administration of Sermorelin peptide may help improve short-term memory.^[12] In fact, the researchers reported that the effect on memory recall appeared more significant in Sermorelin-treated participants than those treated with a placebo. There is also mixed evidence regarding the effects of Sermorelin peptide on brain tumors. One in vitro experiment reports that Sermorelin peptide may speed up the development of neuroendocrine tumors such as pituitary adenomas due to its possible growth-promoting effect.^[13] However, a clinical trial in patients with gliomas reported the opposite effect, observing that the peptide appeared to suppress the recurrence of the tumors.^[14] 

Conclusion

Sermorelin may hold significant research potential as a Growth Hormone Secretagogue (GSH). This is supported by research findings indicating that when administered with Sermorelin, study participants’ serum HGH levels could not exceed the physiological limits exerted by somatostatin. The only adverse effects during therapy are reported to be transitionary local reactions in the administration site, which occur in 1/5 of the patients and include pain, swelling, and redness.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs. 1999 Aug;12(2):139-57. doi: 10.2165/00063030-199912020-00007. PMID: 18031173.
2. Thorner M, Rochiccioli P, Colle M, Lanes R, Grunt J, Galazka A, Landy H, Eengrand P, Shah S. Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. Geref International Study Group. J Clin Endocrinol Metab. 1996 Mar;81(3):1189-96. doi: 10.1210/jcem.81.3.8772599. PMID: 8772599.
3. Neyzi O, Yordam N, Ocal G, Bundak R, Darendeliler F, Açikgöz E, Berberoğlu M, Günöz H, Saka N, Calikoğlu AS. Growth response to growth hormone-releasing hormone(1-29)-NH2 compared with growth hormone. Acta Paediatr Suppl. 1993 Mar;388:16-21; discussion 22. doi: 10.1111/j.1651-2227.1993.tb12828.x. PMID: 8329826.
4. Achermann JC, Hindmarsh PC, Robinson IC, Matthews DR, Brook CG. The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2) and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation: studies in normal and post cranial irradiated individuals. Clin Endocrinol (Oxf). 1999 Nov;51(5):575-85. doi: 10.1046/j.1365-2265.1999.00839.x. PMID: 10594518.
5. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.
6. Chatelain PG, Sanchez P, Saez JM. Growth hormone and insulin-like growth factor I treatment increase testicular luteinizing hormone receptors and steroidogenic responsiveness of growth hormone deficient dwarf mice. Endocrinology. 1991 Apr;128(4):1857-62. doi: 10.1210/endo-128-4-1857. PMID: 2004605.
7. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.
8. Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart KJ, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RG. Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men. Metabolism. 1997 Jan;46(1):89-96. doi: 10.1016/s0026-0495(97)90174-8. PMID: 9005976.
9. Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab. 1992 Aug;75(2):530-5. doi: 10.1210/jcem.75.2.1379256. PMID: 1379256.
10. Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart KJ, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RG. Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men. Metabolism. 1997 Jan;46(1):89-96. doi: 10.1016/s0026-0495(97)90174-8. PMID: 9005976.
11. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.
12. Alvarez XA, Cacabelos R. Effects of GRF (1-29) NH2 on short-term memory: neuroendocrine and neuropsychological assessment in healthy young subjects. Methods Find Exp Clin Pharmacol. 1990 Sep;12(7):493-9. PMID: 2087150.
13. Stepień T, Sacewicz M, Lawnicka H, Krupiński R, Komorowski J, Siejka A, Stepień H. Stimulatory effect of growth hormone-releasing hormone (GHRH(1-29)NH2) on the proliferation, VEGF and chromogranin A secretion by human neuroendocrine tumor cell line NCI-H727 in vitro. Neuropeptides. 2009 Oct;43(5):397-400. doi: 10.1016/j.npep.2009.08.005. Epub 2009 Sep 10. PMID: 19747727.
14. Chang Y, Huang R, Zhai Y, Huang L, Feng Y, Wang D, Chai R, Zhang W, Hu H. A potentially effective drug for patients with recurrent glioma: sermorelin. Ann Transl Med. 2021 Mar;9(5):406. doi: 10.21037/atm-20-6561. PMID: 33842627; PMCID: PMC8033379.

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. 

Conclusion

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.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Ming W, Lu G, Xin S, Huanyu L, Yinghao J, Xiaoying L, Chengming X, Banjun R, Li W, Zifan L. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochem Biophys Res Commun. 2016 Aug 5;476(4):412-419. doi: 10.1016/j.bbrc.2016.05.135. Epub 2016 May 26. PMID: 27237975.
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. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54. doi: 10.1016/j.cmet.2015.02.009. PMID: 25738459; PMCID: PMC4350682.
4. Lu H, Tang S, Xue C, Liu Y, Wang J, Zhang W, Luo W, Chen J. Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation. Int J Mol Sci. 2019 May 17;20(10):2456. doi: 10.3390/ijms20102456. PMID: 31109005; PMCID: PMC6567243.
5. Yin Y, Pan Y, He J, Zhong H, Wu Y, Ji C, Liu L, Cui X. The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. Pharmacol Res. 2022 Jan;175:105987. doi: 10.1016/j.phrs.2021.105987. Epub 2021 Nov 17. PMID: 34798268.
6. Kumagai H, Coelho AR, Wan J, Mehta HH, Yen K, Huang A, Zempo H, Fuku N, Maeda S, Oliveira PJ, Cohen P, Kim SJ. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab. 2021 Apr 1;320(4):E680-E690. doi: 10.1152/ajpendo.00275.2020. Epub 2021 Feb 8. PMID: 33554779; PMCID: PMC8238132.
7. Ran N, Lin C, Leng L, Han G, Geng M, Wu Y, Bittner S, Moulton HM, Yin H. MOTS-c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice. EMBO Mol Med. 2021 Feb 5;13(2):e12993. doi: 10.15252/emmm.202012993. Epub 2020 Dec 18. PMID: 33337582; PMCID: PMC7863382.
8. Zhong P, Peng J, Hu Y, Zhang J, Shen C. Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice. J Cell Mol Med. 2022 Nov;26(21):5369-5378. doi: 10.1111/jcmm.17551. Epub 2022 Sep 25. PMID: 36156853; PMCID: PMC9639045.
9. Wang M, Wang G, Pang X, Ma J, Yuan J, Pan Y, Fu Y, Laher I, Li S. MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats. Front Nutr. 2023 Jan 4;9:1060684. doi: 10.3389/fnut.2022.1060684. PMID: 36687680; PMCID: PMC9846618.
10. Shen C, Wang J, Feng M, Peng J, Du X, Chu H, Chen X. The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways. Cardiovasc Eng Technol. 2022 Oct;13(5):651-661. doi: 10.1007/s13239-021-00589-w. Epub 2021 Dec 2. PMID: 34859377.
11. Wei M, Gan L, Liu Z, Liu L, Chang JR, Yin DC, Cao HL, Su XL, Smith WW. Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway. Cardiorenal Med. 2020;10(1):42-50. doi: 10.1159/000503224. Epub 2019 Nov 6. PMID: 31694019.
12. Yuan J, Wang M, Pan Y, Liang M, Fu Y, Duan Y, Tang M, Laher I, Li S. The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats. Sci Rep. 2021 Oct 11;11(1):20077. doi: 10.1038/s41598-021-99568-3. PMID: 34635713; PMCID: PMC8505603.
13. Yuan J, Xu B, Ma J, Pang X, Fu Y, Liang M, Wang M, Pan Y, Duan Y, Tang M, Zhu B, Laher I, Li S. MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats. Life Sci. 2023 Feb 15;315:121330. doi: 10.1016/j.lfs.2022.121330. Epub 2022 Dec 28. PMID: 36584915.
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