The Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin peptide blend represents a combination of synthetic peptides, each with distinct properties that researchers have hypothesized may hold mechanisms for stimulating growth hormone (GH) synthesis and secretion. Although structurally and functionally unique, these peptides appear to share a common focus on modulating the endocrine system’s GH regulatory axis. This blend has been the subject of various research efforts to explore its biochemical properties, interactions with receptors, and physiological effects.

 

Tesamorelin Peptide

Tesamorelin is a synthetic analog of growth hormone-releasing hormone (GHRH), engineered to resemble the natural peptide that scientists consider to be responsible for stimulating GH secretion. Structurally, Tesamorelin consists of 44 amino acids and incorporates specific modifications to enhance its stability against enzymatic degradation. One notable modification is the introduction of a trans-3-hexenoic acid group at its C-terminus, often referred to as an omega-amino acid modification.^[1] This alteration is hypothesized to improve resistance to enzymatic breakdown, prolonging its functional lifespan in biological systems. Additionally, the N-terminal acetylation (CH₃CO-) has been suggested to further contribute to its structural resilience and bioactivity. These modifications result in the designation N-(trans-3-hexenoyl)-[Tyr1]hGRF(1–44)NH2 acetate.

Tesamorelin’s mechanism of action is thought to involve binding to GHRH receptors located in the hypothalamus and pituitary gland,^[1] thereby triggering the release of endogenous GH. This proposed mechanism has garnered interest in exploring its implications for protein metabolism, lipid oxidation, and cellular growth processes.

 

CJC-1295 (Mod GRF 1-29) Peptide

CJC-1295 (Mod GRF 1-29) is a synthetic derivative of the functional segment of GHRH, comprising 29 amino acids. This peptide is often described as a tetrasubstituted variant designed to resist enzymatic degradation and extend its half-life. Unlike its predecessor with a Drug Affinity Complex (DAC), the Mod GRF 1-29 variant lacks the DAC but appears to have retained significant stability and activity. Research suggests that CJC-1295 interacts with GHRH receptors in the pituitary gland, where it may stimulate GH secretion.

Its proposed mechanism mimics that of GHRH, potentially enhancing protein synthesis, promoting muscle hypertrophy, and influencing metabolic pathways.^[2] The peptide’s engineered design aims to maintain functionality while reducing susceptibility to degradation, making it a key component of this peptide blend.

 

Ipamorelin Peptide

Ipamorelin is a synthetic pentapeptide and a selective agonist for the ghrelin receptor, also known as the growth hormone secretagogue (GHS) receptor. This receptor is predominantly expressed in the pituitary gland, where its activation may stimulate the release of GH. Ipamorelin exhibits high specificity for the GHS receptor, with minimal interaction with other hormonal systems, reducing the likelihood of off-target action.

Research suggests that Ipamorelin’s apparent selective binding to the GHS receptor might enhance GH secretion without altering levels of other hormones, such as cortisol or prolactin.^[3] This unique mechanism positions Ipamorelin as a potential tool for investigating GH-related physiological processes, including growth, repair, and metabolic regulation.

This tri-peptide blend appears to combine Tesamorelin’s GHRH receptor affinity, CJC-1295’s enhanced stability and activity, and Ipamorelin’s selective ghrelin receptor stimulation. Together, these peptides may offer synergistic effects on GH secretion, which warrants further investigation through controlled research studies.

 

Scientific Research and Studies

 

Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin Blend and the Pituitary Gland

The peptide blend comprising Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin is speculated to potentially interact with the pituitary gland, primarily through receptor-specific binding that may modulate the secretion of growth hormone (GH).

Tesamorelin and CJC-1295 (Mod GRF 1-29) are analogs of growth hormone-releasing hormone (GHRH) that appear to target GHRH receptors on somatotrophs in the anterior pituitary. Research suggests that their interaction may induce receptor conformational changes, activating downstream intracellular signaling cascades.^[4] Specifically, these peptides are hypothesized to stimulate adenylate cyclase, leading to the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). The resulting elevation of cAMP levels is thought to activate protein kinase A (PKA), which phosphorylates various intracellular targets. This signaling cascade is believed to culminate in the synthesis and secretion of human growth hormone (hGH). The hGH released from somatotroph cells may also facilitate the production of insulin-like growth factor-1 (IGF-1), deemed a critical mediator of growth hormone activity.

CJC-1295 (Mod GRF 1-29) exhibits notable structural modifications, including four amino acid substitutions, which may enhance its resistance to enzymatic degradation. This increased stability is reported to extend its half-life, improving its pharmacokinetic profile. Additionally, these modifications allow a proportion of the peptide to covalently bind to serum albumin, thereby prolonging its duration of action. Trace binding to fibrinogen and immunoglobulin G (IgG) has also been observed. These properties collectively suggest a sustained mechanism of action, with a potential for increased biological activity.^[5]

Ipamorelin, in contrast, is a selective agonist for the ghrelin receptor, also referred to as the growth hormone secretagogue receptor (GHSR). This peptide is believed to bind to GHSR on somatotroph cells, initiating signaling pathways that may promote GH secretion. Unlike some other secretagogues, Ipamorelin appears to exert a high degree of specificity for GHSR, with apparently minimal off-target effects on other endocrine pathways, including prolactin and adrenocorticotropic hormone (ACTH) regulation.^[6]

In vitro studies^[7] suggest that Ipamorelin binding to GHSR activates phospholipase C (PLC), which catalyzes the generation of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 may mobilize calcium ions (Ca2+) from intracellular stores, while DAG is thought to activate protein kinase C (PKC). These intracellular events potentially facilitate the exocytosis of vesicles containing GH from somatotroph cells. This process underscores the peptide’s role in GH secretion through precise intracellular signaling mechanisms.

The combined properties of Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin suggest a synergistic effect on pituitary function. Tesamorelin and CJC-1295 (Mod GRF 1-29) focus on GHRH receptor pathways, while Ipamorelin appears to activate the GHSR, providing complementary mechanisms to stimulate GH release. These peptides collectively indicate complex interactions with the pituitary gland, potentially enhancing GH secretion through distinct yet interconnected molecular pathways. Such findings highlight their potential implications in regulating growth hormone activity and associated metabolic processes. Further research is necessary to elucidate the full scope of their physiological effects and research applications.

 

Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin and Cardiovascular Action

The potential cardiovascular effects of Tesamorelin, Modified GRF (CJC-1295), and Ipamorelin have been studied with an emphasis on cardiac repair and lipid metabolism. Following myocardial infarction (MI), cardiac tissue often undergoes scarring, which can impair heart function, including ejection fraction and contractility. Research in animal models suggests that growth hormone secretagogues may possibly enhance post-MI cardiac repair. Observed outcomes include reduced infarct size, improved cardiac ejection fraction, and restoration of overall cardiac function.^[8]

Ipamorelin’s activation of the GHS-R1a receptor is hypothesized to exert a possible cardioprotective effect through positive inotropic properties. Researchers elucidate that, “Through activation of GHS-R1a, secretagogues produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury, likely by safeguarding or restoring p-PLB (and hence SR Ca2+ content) to facilitate the maintenance or recovery of normal cardiac contractility.”

Additionally, Tesamorelin, while primarily recognized for its lipodystrophy-reducing properties, has exhibited potential cardiovascular action, particularly in HIV-positive models. Some studies highlight its potential to lower triglycerides, total cholesterol, and non-HDL cholesterol levels,^[9] suggesting a broader impact on lipid metabolism and cardiovascular function. These findings collectively underscore the potential of this peptide blend to modulate cardiac function and lipid profiles.

 

Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin and Effect on Gastrointestinal Tract

The peptide blend comprising Tesamorelin, Modified GRF (CJC-1295), and Ipamorelin may hold varying degrees of influence on the gastrointestinal (GI) tract through distinct mechanisms. Tesamorelin appears to enhance gastric emptying and gastrointestinal motility, as observed in preclinical studies. This action suggests its potential utility in addressing motility disorders or delayed gastric emptying.

Modified GRF, while exhibiting minimal direct effects on motility, appears to support GI function by improving gut barrier integrity and mitigating intestinal inflammation. This effect has been primarily studied in animal models of colitis, where the peptide appeared to host anti-inflammatory properties and potential contributions to the restoration of gut homeostasis.

Ipamorelin, as a selective agonist of the ghrelin receptor, is posited to exert effects through receptor activation within the GI tract. Upon binding to ghrelin receptors, Ipamorelin may stimulate gut motility, improve nutrient absorption, and contribute to tissue repair following gastrointestinal injury. Furthermore, preclinical research indicates its potential to mitigate inflammation and promote recovery in various models of GI injury. According to the studies, Ipamorelin may “increase total body fat percentages,” suggesting the peptide is a “potent and selective stimulator of GH that [may] significantly influence the GI system, body composition, and adiposity.”^[10]

 

Synergistic Potential of Tesamorelin, CJC-1295 (Mod GRF 1-29), and Ipamorelin Peptides

The combination of Tesamorelin, Modified GRF (CJC-1295), and Ipamorelin has been proposed by its researchers to enhance growth hormone (GH) secretion through distinct yet complementary mechanisms of action. Studies suggest that Tesamorelin and Modified GRF, when combined, may produce a synergistic increase in GH levels, surpassing the effects of either peptide alone.^[11] This blend is also speculated to cause reductions in visceral adipose tissue, particularly in models of HIV-associated lipodystrophy, though this effect may have been reversed upon study cessation.

Beyond GH secretion, this peptide combination, as per the research, is suggested to support improved sleep-wake cycles, increased behavioral mood, energy, and sustained GH production over time. Together, these peptides may also synergistically enhance insulin-like growth factor 1 (IGF-1) levels, potentially leading to improved muscle growth, bone density, cognitive function, and cellular repair, making this blend a promising tool for studies exploring diverse metabolic and physiological challenges.

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. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 9831659, Ipamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Ipamorelin.
2. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 56841945. https://pubchem.ncbi.nlm.nih.gov/compound/56841945.
3. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 16137828, Tesamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Tesamorelin
4. Spooner, L. M., & Olin, J. L. (2012). Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. The Annals of pharmacotherapy, 46(2), 240–247. https://doi.org/10.1345/aph.1Q629
5. Zhou, F., Zhang, H., Cong, Z., Zhao, L. H., Zhou, Q., Mao, C., Cheng, X., Shen, D. D., Cai, X., Ma, C., Wang, Y., Dai, A., Zhou, Y., Sun, W., Zhao, F., Zhao, S., Jiang, H., Jiang, Y., Yang, D., Eric Xu, H., … Wang, M. W. (2020). Structural basis for activation of the growth hormone-releasing hormone receptor. Nature communications, 11(1), 5205. https://doi.org/10.1038/s41467-020-18945-0
6. Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108996/
7. Jiménez-Reina, L., Cañete, R., de la Torre, M. J., & Bernal, G. (2002). Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histology and histopathology, 17(3), 707–714. https://doi.org/10.14670/HH-17.707
8. Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C. Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One. 2012;7(4):e35265. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035265 Epub 2012 Apr 6. PMID: 22493744; PMCID: PMC3320867. https://pmc.ncbi.nlm.nih.gov/articles/PMC3320867/
9. Stanley TL, Falutz J, Marsolais C, Morin J, Soulban G, Mamputu JC, Assaad H, Turner R, Grinspoon SK. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis. 2012 Jun;54(11):1642-51. doi: 10.1093/cid/cis251. Epub 2012 Apr 10. PMID: 22495074; PMCID: PMC3348954. https://pubmed.ncbi.nlm.nih.gov/22495074/
10. Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108996/
11. Bedimo R. Growth hormone and tesamorelin in the management of HIV-associated lipodystrophy. HIV AIDS (Auckl). 2011;3:69-79. doi: 10.2147/HIV.S14561. Epub 2011 Jul 10. PMID: 22096409; PMCID: PMC3218714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218714/

Liraglutide is a synthetic analog of the glucagon-like peptide-1 (GLP-1), an endogenous incretin hormone known for its potential role in regulating glucose metabolism and appetite.^[1] Classified as a lipopeptide, Liraglutide peptide is suggested to be structurally similar to GLP-1, sharing 97% homology with its natural counterpart and containing 31 amino acids, including an arginine residue and a hexadecanoyl group. Originally developed to address the limitations of native GLP-1’s short half-life, Liraglutide peptide was reportedly engineered to achieve prolonged activity.

The development of Liraglutide peptide began with the discovery of GLP-1, an incretin hormone believed to stimulate insulin secretion and lower postprandial glucose levels. This discovery appeared to have spurred research into synthetic GLP-1 receptor agonists, culminating in the creation of Liraglutide peptide. Preclinical studies have since suggested that the peptide may be efficient in improving glycemic control, reducing weight, and thereby potentially mitigating cardiovascular risks.

The actions of Liraglutide are speculated to be mediated through its interaction with GLP-1 receptors (GLP-1R), which are widely expressed in pancreatic beta cells, the gastrointestinal tract, and the central nervous system. Upon binding to GLP-1R, Liraglutide peptide may initiate several signaling cascades that contribute to its possible diverse physiological functions.

Glucose-Dependent Insulin Secretion

Liraglutide appears to activate GLP-1R on pancreatic beta cells, possibly facilitating insulin release in response to elevated blood glucose levels.^[2] This reported glucose-dependent mechanism may minimize the risk of hypoglycemia, a significant advantage over traditional insulin studies.

Glucagon Secretion

By potentially suppressing glucagon release from pancreatic alpha cells, Liraglutide is speculated to reduce hepatic glucose production, possibly contributing to improved glycemic control.^[1]

Gastric Emptying

Liraglutide appears to slow gastric motility, prolonging nutrient absorption and satiety. This effect is hypothesized to play a role in appetite regulation.

Neuroendocrine Action

GLP-1R activation in the central nervous system has been linked to appetite suppression and potential enhancements in cognitive functions, as suggested by preclinical studies.^[3]

Beta Cells

Research suggests that Liraglutide may stimulate the proliferation and differentiation of pancreatic beta cells, protecting them from apoptosis and promoting their long-term function.

Cardioprotective Potential

GLP-1R is also expressed in cardiac tissue, where Liraglutide may exert protective potential. Studies suggest its involvement in glucose uptake within cardiac muscles, potentially reducing ischemic damage and supporting myocardial survival.^[4]

 

Scientific Research and Studies

 

Liraglutide Peptide and the Incretin Effect

The Incretin Effect, as characterized by Dr. Holst, is a physiological mechanism mediated by glucagon-like peptide-1 (GLP-1), a metabolic hormone released by the gastrointestinal (GI) tract. Incretins, including GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), appear to play potential roles in lowering blood glucose levels through their perceived glucose-dependent stimulation of insulin secretion. Among these, GLP-1 is posited to exhibit superior potency compared to GIP, particularly under hyperglycemic conditions, despite circulating at significantly lower concentrations—approximately tenfold less than GIP.

A notable study^[1] conducted in 2007 studied the introduction of Liraglutide peptide in isolated rat pancreases pre-exposed to sulfonylurea drugs. The findings suggested that while GLP-1 introduction under low glucose concentrations had minimal effects on insulin secretion, prior exposure to sulfonylurea compounds significantly amplified the insulinotropic response. The study reported a “dramatic stimulation of insulin secretion” under these conditions. Moreover, clinical data suggest that “30–40% of [research models exposed to] both sulfonyl urea compounds and a GLP-1 agonist (exendin 4) experience, usually mild, hypoglycemia”, underscoring the conceivably synergistic interaction between these two agents.

This study suggests the possible role of GLP-1 in the incretin effect and suggests that Liraglutide’s efficacy may be further optimized when studied alongside agents that may sensitize pancreatic beta cells, such as sulfonylureas.

 

Obesity

Research utilizing murine models has suggested that exposure to glucagon-like peptide-1 (GLP-1) and its analogs, such as GLP-1 receptor agonists (GLP-1RAs) like Liraglutide peptide, directly into the central nervous system may result in a reduction in appetite and food consumption. This observation suggests that these peptides may increase satiety signaling pathways, contributing to a sensation of fullness and a subsequent decrease in caloric intake.^[5]

Recent preclinical investigations have further reported that the twice-daily exposure of GLP-1RAs in mice may produce gradual and sustained weight loss over time. This reduction in body weight may also correlate with improvements in cardiovascular risk factors and a decline in hemoglobin A1C levels, a biomarker commonly employed to evaluate long-term glycemic control and the perceived effectiveness of diabetes management resources. These findings suggest the multifaceted metabolic potential associated with Liraglutide peptide and its hypothesized capacity to influence both weight and associated physiological outcomes.

 

Liraglutide Peptide and Gastric Motility

Investigations suggest that exposure to Liraglutide peptide may result in a 23% reduction in gastric emptying within the first hour postprandially, compared to placebo. However, no significant difference was observed in the 5-hour gastric emptying time between Liraglutide peptide and the placebo. This transient postprandial delay in gastric motility may still be sufficient to enhance early satiety.^[6]

The mechanisms underlying Liraglutide’s effect on gastric motility are hypothesized to be multifactorial, involving complex neural and hormonal interactions. Liraglutide peptide appears to engage GLP-1 receptors (GLP-1Rs) located both within the central nervous system (CNS) and the peripheral nervous system. Activation of GLP-1Rs on enteroendocrine cells in the gastrointestinal tract, which appear responsive to nutrient intake, likely mimics and enhances the physiological actions of endogenous GLP-1.

Upon activation, these receptors may initiate signaling through the enteric nervous system, which governs gastrointestinal motility. This signaling is thought to regulate the contractile activity of the stomach, thereby slowing the rate at which gastric contents are released into the small intestine. Concurrently, Liraglutide-mediated activation of GLP-1Rs may also engage the vagal nerve, transmitting signals to the CNS. This central pathway may further modulate autonomic feedback mechanisms that influence gastric motility, reinforcing the peptide’s potential to reduce the rate of gastric emptying. These processes collectively highlight the sophisticated interplay between peripheral and central mechanisms in mediating Liraglutide’s effects on gastric motility.^[7]

 

Liraglutide Peptide and Beta Cells

Research utilizing animal models suggests that glucagon-like peptide-1 (GLP-1) and its analogs, such as Liraglutide peptide, may exert significant effects on the proliferation and growth of pancreatic beta cells. Additionally, GLP-1 analogs like Liraglutide peptide are hypothesized to facilitate the differentiation of beta cells from progenitor cells within the epithelial lining of the pancreatic duct. These peptides may also inhibit beta-cell apoptosis, thereby altering the balance between beta-cell growth and death in favor of cell survival and expansion.^[8]

The cumulative data suggests that Liraglutide peptide may play a role in maintaining beta cell mass and function, which may aid in diabetes-related studies. By promoting beta cell proliferation and differentiation while concurrently reducing apoptosis, Liraglutide peptide may contribute to preserving pancreatic function and mitigating damage to beta cells caused by metabolic or inflammatory insults.

Furthermore, a pivotal study suggested that Liraglutide peptide may mitigate beta cell death triggered by elevated levels of pro-inflammatory cytokines. Experimental models of type 1 diabetes in mice have indicated that GLP-1 analogs may protect pancreatic islet cells, potentially delaying or preventing the onset of autoimmune beta cell destruction associated with type 1 diabetes. These findings underscore the potential of Liraglutide peptide as a protective agent within research related to beta cells.^[8]

 

Liraglutide Peptide and Cardiovascular Impact

The distribution of glucagon-like peptide-1 (GLP-1) receptors throughout cardiac tissue suggests a potential role for GLP-1 and its analogs, such as Liraglutide peptide, in modulating cardiac function. Based on the studies, it appears that GLP-1 receptor activation may potentially increase heart rate and reduce left ventricular end-diastolic pressure, mechanisms that might mitigate left ventricular hypertrophy, cardiac remodeling, and the progression to heart failure.^[9]

Emerging data suggest that GLP-1 and related peptides may reduce myocardial damage during ischemic events such as myocardial infarction. These peptides appear to facilitate glucose uptake in cardiac myocytes, thereby supplying ischemic myocardial cells with critical nutrients. This glucose uptake is noted to occur independently of insulin, highlighting a unique cardioprotective mechanism. By supporting cellular metabolism and reducing apoptosis, GLP-1 receptor agonists like Liraglutide peptide may help preserve myocardial integrity in ischemic conditions.

Studies in canine models, where GLP-1 was introduced in significant quantities, reportedly exhibited improvement in left ventricular performance and reported decrease systemic vascular resistance. These effects contribute to reductions in blood pressure and myocardial strain, potentially alleviating hypertension-related complications such as ventricular remodeling, vascular thickening, and heart failure.

Nikolaidis et al. reported “rGLP-1 dramatically improved LV and systemic hemodynamics in dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.” ^[10]

 

Neuroprotection

Recent findings suggest that glucagon-like peptide-1 (GLP-1) and its analogs, may hold significant neuroprotective potential. GLP-1 receptor activation has been associated with improved cognitive functions, including learning and memory, and may provide protection against neurodegenerative conditions such as Alzheimer’s disease.

Experimental studies have reported that GLP-1 appears to enhance associative and spatial learning in murine models and may possibly mitigate learning deficits in mice with specific genetic abnormalities. Notably, rats with increased expression of GLP-1 receptors in distinct brain regions exhibited superior learning and memory performance compared to control groups. This suggests a link between GLP-1 receptor activity and improved cognitive capacity.^[11]

In addition to cognitive potential, GLP-1 analogs like Liraglutide peptide have been suggested by researchers to exert protective effects against excitotoxic neuronal damage. Research using rat models of neurodegeneration has revealed that Liraglutide peptide may provide fairly robust protection against glutamate-induced apoptosis, a key mechanism underlying neuronal loss in neurodegenerative disorders.^[12] Furthermore, in vitro studies appear to suggest that GLP-1 analogs may promote neurite outgrowth, indicating a role in neural regeneration and repair.

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. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006. PMID: 17928588. https://pubmed.ncbi.nlm.nih.gov/17928588/
2. Tandong Yang, Meng Chen, Jeffrey D. Carter, Craig S. Nunemaker, James C. Garmey, Sarah D. Kimble, Jerry L. Nadler, Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes, Biochemical and Biophysical Research Communications, Volume 344, Issue 3, 2006, Pages 1017-1022, ISSN 0006-291X, https://www.sciencedirect.com/science/article/pii/S0006291X06007066
3. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. https://pubmed.ncbi.nlm.nih.gov/16776751/
4. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005. https://pubmed.ncbi.nlm.nih.gov/15616022/
5. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. https://pubmed.ncbi.nlm.nih.gov/16776751/
6. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog Liraglutide peptide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014 Jun;38(6):784-93. doi: 10.1038/ijo.2013.162. Epub 2013 Sep 3. PMID: 23999198; PMCID: PMC4052428. https://pmc.ncbi.nlm.nih.gov/articles/PMC4052428/
7. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018 Apr 3;27(4):740-756. doi: 10.1016/j.cmet.2018.03.001. PMID: 29617641. https://pubmed.ncbi.nlm.nih.gov/29617641/
8. Tandong Yang, Meng Chen, Jeffrey D. Carter, Craig S. Nunemaker, James C. Garmey, Sarah D. Kimble, Jerry L. Nadler, Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes, Biochemical and Biophysical Research Communications, Volume 344, Issue 3,  2006, Pages 1017-1022, ISSN 0006-291X, https://www.sciencedirect.com/science/article/pii/S0006291X06007066)
9. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005. https://pubmed.ncbi.nlm.nih.gov/15616022/
10. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004 Aug 24;110(8):955-61. https://pubmed.ncbi.nlm.nih.gov/15313949/
11. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep; https://pubmed.ncbi.nlm.nih.gov/12925848
12. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. doi: 10.1124/jpet.102.037481. PMID: 12183643. https://pubmed.ncbi.nlm.nih.gov/12183643/

The Modified GRF 1-29 and Ipamorelin blend represents a significant advancement in peptide-based research, particularly for its potential to influence growth hormone secretion and metabolic processes. This synergistic combination pairs two complementary peptides with distinct but interconnected roles, which is considered pivotal in this branch of scientific research.

Modified GRF 1-29, a stabilized analog of growth hormone-releasing hormone (GHRH), is reportedly designed to increase growth hormone release by targeting GHRH receptors on somatotroph cells in the anterior pituitary gland.^[1] Its structural modifications, which replace four amino acids in the native sequence, are speculated to confer enhanced stability and bioavailability, potentially making it more resistant to enzymatic degradation.

Ipamorelin, a synthetic pentapeptide and selective growth hormone secretagogue (GHS), is suggested to operate by mimicking the action of ghrelin, a naturally occurring hormone involved in hunger signaling and growth hormone release. By activating growth hormone secretagogue receptor 1-alpha (GHS-R1a) in the pituitary, Ipamorelin reportedly initiates intracellular signaling pathways that stimulate the secretion of growth hormone while maintaining high selectivity to avoid affecting other hormones such as cortisol or prolactin.

Together, these peptides are speculated to offer a powerful mechanism of action where Ipamorelin may provide rapid, short-term stimulation of growth hormone release, while Modified GRF 1-29 may ensure a more sustained response by activating complementary signaling pathways. This dual-action mechanism, achieved through distinct receptor interactions, might create an extended-release profile that researchers suggest may lead to increased growth hormone activity compared to studying either peptide alone.^[2]

 

Scientific Research and Studies

 

Modified GRF 1-29 & Ipamorelin Blend and Growth Hormone

A series of studies^[3] conducted in 1998 appears to provide critical insights into the function of the Modified GRF 1-29 and Ipamorelin blend in the function of growth hormone secretion. Experimental models, including rat pituitary glands, anesthetized rats, and conscious swine, were utilized to evaluate the peptides’ activity. Findings suggest that both Modified GRF 1-29 and Ipamorelin may act as agonists of GHRP-like receptors, binding to these targets to reportedly stimulate significant increases in growth hormone secretion. It also appears that the peptides exhibited high receptor specificity. While other growth hormone secretagogues often triggered elevations in additional hormones such as cortisol and ACTH, Ipamorelin and Modified GRF 1-29 “very surprisingly, did not [appear to] release ACTH or cortisol in levels significantly”, reportedly even at significantly high concentrations compared to other similar peptides.

Further research in 1999 sought to extend these findings through clinical trials. In this study,^[4] eight research models were introduced with growth hormone secretagogues at progressively increasing concentrations, with amounts adjusted every 15 minutes over a two-hour period. Based on the results, it was suggested that there was a marked elevation in circulating growth hormone levels throughout the study duration, suggesting a concentration-dependent response to the blend.

These findings support the hypothesis that the combination of Modified GRF 1-29 and Ipamorelin may provide a synergistic and sustained increase of growth hormone release, laying the groundwork for future research into their potential.

 

Cardiac Function

In a pilot study,^[5] experimental models were introduced with growth hormone-releasing hormone (GHRH) peptide analogs, including Modified GRF 1-29, to evaluate their potential effects on cardiac function. Findings from this research suggest that the peptides may positively influence myocardial function, particularly in models of myocardial infarction. The study hypothesized that Modified GRF 1-29 might enhance cardiac performance by increasing heart rate and improving blood pumping efficiency.

 

Modified GRF 1-29 & Ipamorelin Blend and Potency

Preliminary investigations have provided significant hypotheses into the potency of the Modified GRF 1-29 and Ipamorelin blend, specifically its potential compared to regular GRF 1-29. In one study,^[6] experimental rats were exposed to GHRH peptide analogs, including Modified GRF 1-29. Results suggested that the synthetic analog may have greater efficacy in stimulating growth hormone release than its unmodified counterpart. This enhanced potency appears to be attributed to the structural modifications in Modified GRF 1-29, which may improve its stability and receptor binding efficiency, allowing for sustained biological activity over time.

 

Modified GRF 1-29 & Ipamorelin Blend and the Pituitary

The efficacy of the blend in promoting growth hormone secretion is closely linked to its interaction with GHRH receptors on somatotroph cells in the anterior pituitary gland. The binding of the peptide to these receptors is hypothesized to act as a catalyst for a cascade of intracellular signaling events. One such pathway involves the activation of adenylyl cyclase, which converts ATP into cyclic adenosine monophosphate (cAMP). The elevation of cAMP levels activates protein kinase A (PKA), leading to the phosphorylation of proteins, such as voltage-dependent calcium channels on the somatotroph cell membrane.^[7] This phosphorylation facilitates calcium ion influx, which reportedly initiates the secretion of growth hormone from the cell’s secretory vesicles into the bloodstream.

Similarly, Ipamorelin appears to function with a distinct mechanism of action by selectively targeting the GHS-R1a receptors in the anterior pituitary. The peptide supposedly interacts with the N-terminal region of these receptors through hydrogen bonding and van der Waals forces, inducing conformational changes that activate intracellular G-protein signaling pathways. Specifically, GHS-R1a is thought to couple with Gαq/11 subunits, which subsequently activate phospholipase C (PLC). PLC cleaves phosphatidylinositol 4, 5-bisphosphate (PIP2) into two critical secondary messengers: inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to receptors on the endoplasmic reticulum, prompting the release of calcium ions (Ca2+), which, in turn, reportedly activates downstream proteins that regulate growth hormone secretion.^[8]

 

Modified GRF 1-29 & Ipamorelin Blend and the Gastrointestinal System

In a recent investigation, the potential influence of Ipamorelin on gastric motility was examined, with particular emphasis on its capacity to expedite gastric emptying. The study utilized a specialized technique to assess gastric emptying by quantifying the percentage of radioactivity remaining in the stomach 15 minutes following the introduction of a radiolabeled substance via intragastric gavage. The researchers observed that surgical manipulation of the abdominal region may have contributed to a delayed gastric emptying rate, as reported by the researchers in the control group, which received a vehicle substance. In contrast, Ipamorelin appeared to significantly accelerate the gastric emptying process relative to the control group, suggesting that Ipamorelin may potentially increase the rate of gastric emptying.

Subsequent analyses studied the possible effect of Ipamorelin on the contractile activity of gastric smooth muscle, which was induced by both acetylcholine and electrical field stimulation. The results suggested that surgical intervention and manipulation of the gastrointestinal tract in these animal models may markedly attenuate the contractile responses of gastric smooth muscle to these stimuli. Notably, this suppression appeared to be reversed when both Ipamorelin and ghrelin were co-introduced, hinting that Ipamorelin may not only facilitate gastric smooth muscle contractility but also potentially mitigate any inhibitory effects induced by certain surgical interventions.^[9]

 

Modified GRF 1-29 & Ipamorelin Blend and Appetite Regulation

The potential effects of Ipamorelin on ghrelin receptors suggest a potential for appetite support and subsequent weight increase In a controlled study,^[10] experimental models reportedly “induced a small (15%) increase in body weight by 2 weeks” following peptide exposure. Researchers propose that this compound may have disproportionately increased fat pad mass relative to total body mass, which may lead to a discernible rise in fat as measured by dual-energy X-ray absorptiometry (DEXA). Further data indicated that Ipamorelin may have elevated serum leptin levels, a hormone associated with energy balance and appetite regulation. This observation has led to the hypothesis that increased food intake may play a role in the observed weight gain in the Ipamorelin-exposed research models. The researchers suggest that growth hormone secretagogues (GHSs), such as Ipamorelin, may contribute to fat cell accumulation via mechanisms independent of growth hormone, potentially including an increase in caloric consumption.

 

Modified GRF 1-29 & Ipamorelin Blend and Bone Density

In a study conducted with murine models, the effects of Ipamorelin on bone mass were evaluated through the introduction of both Ipamorelin and a control substance. Real-time DEXA was utilized to monitor alterations in bone mineral content, focusing on specific regions such as the femur and L6 vertebrae. Upon completion of the experimental period, mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans were performed on the femurs of the models under observation. Preliminary findings suggest that Ipamorelin may be associated with an increase in weight and a potential rise in bone mineral content (BMC) in the tibia and vertebrae, as indicated by DEXA results when compared to the control group. Moreover, pQCT data point to an increase in cortical BMC, likely due to an expansion of the bone’s cross-sectional area. The researchers also hypothesize that minor stimulatory effects on linear bone growth may not have been statistically significant in the growth hormone (GH) and Ipamorelin-exposed cohorts, potentially due to the scope of the study.

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. The Discovery of Growth Hormone-Releasing Hormone: An Update https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01740.x
2. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999 Sep;16(9):1412-6. doi: 10.1023/a:1018955126402. PMID: 10496658. https://pubmed.ncbi.nlm.nih.gov/10496658/
3. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822. https://pubmed.ncbi.nlm.nih.gov/9849822/
4. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999 Sep;16(9):1412-6. doi: 10.1023/a:1018955126402. PMID: 10496658. https://pubmed.ncbi.nlm.nih.gov/10496658/
5. Schally AV, Zhang X, Cai R, Hare JM, Granata R, Bartoli M. Actions and Potential Therapeutic Applications of Growth Hormone-Releasing Hormone Agonists. Endocrinology. 2019 Jul 1;160(7):1600-1612. doi: 10.1210/en.2019-00111. PMID: 31070727. https://pubmed.ncbi.nlm.nih.gov/31070727/
6. Schally AV, Zhang X, Cai R, Hare JM, Granata R, Bartoli M. Actions and Potential Therapeutic Applications of Growth Hormone-Releasing  Hormone Agonists. Endocrinology. 2019 Jul 1;160(7):1600-1612. https://pubmed.ncbi.nlm.nih.gov/31070727/
7. Sinha, D. K., Balasubramanian, A., Tatem, A. J., Rivera-Mirabal, J., Yu, J., Kovac, J., Pastuszak, A. W., & Lipshultz, L. I. (2020). Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational andrology and urology, 9(Suppl 2), S149–S159.  https://doi.org/10.21037/tau.2019.11.30
8. Bill, C. A., & Vines, C. M. (2020). Phospholipase C. Advances in experimental medicine and biology, 1131, 215–242. https://doi.org/10.1007/978-3-030-12457-1_9
9. Lall, S., Tung, L. Y., Ohlsson, C., Jansson, J. O., & Dickson, S. L. (2001). Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochemical and biophysical research communications, 280(1), 132–138. https://doi.org/10.1006/bbrc.2000.4065
10. Sabrina Lall, Loraine Y.C Tung, Claes Ohlsson, John-Olov Jansson, Suzanne L Dickson, Growth Hormone (GH)-Independent Stimulation of Adiposity by GH Secretagogues, Biochemical and Biophysical Research Communications, Volume 280, Issue 1, 2001, Pages 132-138, ISSN 0006-291X, https://doi.org/10.1006/bbrc.2000.4065
11. Image 1 source: National Center for Biotechnology Information. PubChem Compound Summary for CID 91976842, CJC1295 Without DAC. https://pubchem.ncbi.nlm.nih.gov/compound/CJC1295-Without-DAC
12. Image 2 source: National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 9831659, Ipamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Ipamorelin.

AHK-Cu is often described as a small tripeptide (alanine–histidine–lysine) that may incorporate a copper ion bound to the residues of alanine and histidine.^[1] Some researchers believe that the amino acid sequence might be endogenously occurring. Investigations by qualified researchers also propose that AHK-Cu peptide might have a role in modulating several processes in endothelial cells, such as hair follicle cells, such as growth, differentiation, and programmed cell death.

 

Mechanism of Action

AHK-Cu peptide has been examined for its possible involvement in hair growth and the maintenance of dermal tissue. In some studies, it appears to act on fibroblasts, which are cells that might produce and maintain the extracellular matrix (ECM)—a complex network of proteins, including collagen and elastin, that provides structural support around cells. Fibroblasts may also secrete certain signaling molecules, such as Vascular Endothelial Growth Factor (VEGF). Fibroblasts are typically recognized as cells that may synthesize essential structural proteins, including collagen. VEGF refers to a protein family that may be crucial for forming new blood vessels, a process termed angiogenesis. By increasing VEGF production, AHK-Cu peptide might strengthen blood vessel formation, possibly supporting how nutrients and oxygen are delivered to various tissues, including hair follicles.^[2] This route may be relevant for hair growth, as additional nutrients and oxygen may theoretically support follicle function.

AHK-Cu peptide has also been linked to a possible influence on Transforming Growth Factor Beta 1 (TGF-β1). TGF-β1, sometimes viewed as a critical cytokine, is studied for its role in cell growth, immune regulation, and wound repair. If AHK-Cu peptide happens to lower TGF-β1 levels, it might modify certain cell processes or immune responses, though the extent of this potential remains speculative. Because AHK-Cu peptide contains a copper ion, it might engage in enzymatic pathways that influence collagen and elastin production. Collagen and elastin are ECM proteins that may help maintain skin structure elasticity and structural stability. Copper ions themselves have been explored for possible antioxidant activity, which may mean they scavenge free radicals or support other protective mechanisms in cells.
 

Scientific Research and Studies

 

AHK-Cu Peptide and Hair Follicles

In a recent study ^[3], the researchers examined whether AHK-Cu peptide might influence hair growth in laboratory settings. They observed that this peptide may support the elongation of hair follicles and might also encourage the proliferation of dermal papilla cells (DPCs). DPCs are often viewed as specialized fibroblasts with a suggested capacity to promote hair follicle maturation. The same study additionally proposed that AHK-Cu peptide may reduce the frequency of apoptotic (programmed cell death) DPCs. Subsequent analyses indicated that the peptide might elevate the ratio of Bcl-2 (B-cell lymphoma 2) to Bax (Bcl-2-associated X protein). Bcl-2 is frequently seen as an anti-apoptotic factor that may impede cell death, whereas Bax is thought to be pro-apoptotic and might contribute to cell death pathways.

Investigators further speculated that AHK-Cu peptide might decrease cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP) levels—biomolecules often evaluated as markers of cell death. Because a higher Bcl-2/Bax ratio is commonly associated with fewer apoptotic events, the study proposed that such a shift in the ratio may favor cell survival and possibly maintain viable DPC populations. Ultimately, the authors concluded the following: “The present study proposed that AHK-Cu promotes the growth of […] hair follicles, and this stimulatory effect may occur due to stimulation of the proliferation and the preclusion of the apoptosis of DPCs.”^[3]

 

AHK-Cu Peptide and Antioxidative Potential

AHK-Cu is frequently mentioned as having strong antioxidant properties, potentially attributable to its distinctive tripeptide structure, which includes alanine, histidine, and lysine, often bound to a copper ion. Based on these purported antioxidant characteristics, some investigations have posited that AHK-Cu peptide may help protect and restore hair follicle size, ultimately increasing hair growth.

Scientists also speculate that AHK-Cu’s antioxidant potential might have broader functions, possibly involving cellular aging, wound repair, and related physiological processes. These observations reflect the notion that AHK-Cu peptide might help protect collagen from oxidative stress and damage. Collagen—a principal protein for upholding tissue integrity—is often viewed as indispensable for dermal layer and hair cell integrity and overall functionality.^[4]

 

AHK-Cu Peptide and Dermal Cells

Preliminary laboratory work has indicated that “AHK-Cu increases the growth and viability of dermal fibroblasts while stimulating the production of collagen.” Observations suggest that, in certain experiments, the presence of AHK peptide alone appeared to promote both fibroblast viability and replication, in addition to supporting the production of collagen type I.

Investigations measuring collagen type I levels after exposing normal dermal fibroblasts to different AHK concentrations suggested a marked rise in collagen synthesis, which was at times documented to be around threefold compared to control groups.^[5] These findings point to the possibility that AHK might help replenish or maintain the extracellular matrix, which comprises various proteins that form the supportive framework of tissues. By theoretically impacting collagen levels in dermal fibroblasts, AHK-Cu peptide might aid dermal layer functionality, although researchers continue to explore the extent of its potential.

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. Kapoor R, Shome D, Vadera S, Kumar V, Ram MS. QR678 & QR678 Neo Hair Growth Formulations: A Cellular Toxicity & Animal Efficacy Study. Plast Reconstr Surg Glob Open. 2020 Aug 25;8(8):e2843. doi: 10.1097/GOX.0000000000002843. PMID: 32983753; PMCID: PMC7489598.
2. Sadgrove NJ, Simmonds MSJ. Topical and nutricosmetic products for healthy hair and dermal anti-aging using “dual-acting” (2 for 1) plant-based peptides, hormones, and cannabinoids. FASEB Bioadv. 2021 Jun 6;3(8):601-610. doi: 10.1096/fba.2021-00022. PMID: 34377956; PMCID: PMC8332470.
3. Pyo HK, Yoo HG, Won CH, Lee SH, Kang YJ, Eun HC, Cho KH, Kim KH. The effect of tripeptide-copper complex on human hair growth in vitro. Arch Pharm Res. 2007 Jul;30(7):834-9. doi: 10.1007/BF02978833. PMID: 17703734.
4. Kecel-Gunduza, S., Kocb, E., Bicaka, B., Kokcub, Y., Ozela, A. E., & Akyuzc, S. (2020). IN SILICO ANALYSIS FOR CHARACTERIZING THE STRUCTURE AND BINDING PROPERTIES OF ALA-HIS-LYS (AHK) TRIPEPTIDE. The Online Journal of Science and Technology-July, 10(3).
5. Patt, L. M., & Procyte, A. (2009). Neova® DNA Repair Factor Nourishing Lotion Stimulates Collagen and Speeds Natural Repair Process. skin, 1, 2.

Mechano-growth factor (MGF) is posited to be a short, 24–24-amino-acid segment that may appear within one of the isoforms of insulin-like growth factor-1 (IGF-1).^[1] For context, IGF-1 is widely regarded as one of the most powerful endogenous factors driving cellular growth and proliferation. One of its isoforms produced via the IGF-1 gene appears to be the IGF-IEc (otherwise referred to as full-length MGF) isoform. Once produced, this isoform might be cleaved to generate both mature IGF-I—a 70–amino-acid protein common to all IGF-I isoforms—and a distinct 24–amino-acid peptide termed as “MGF.” The name MGF is based on observations that IGF-IEc gene expression may become upregulated when muscle cells are subjected to mechanical stress (for example, exercise). MGF is also termed MGF-Ct24E, MGF-24aa-E, or E-domain of IGF-1Ec. However, endogenous MGF has not been isolated. In research models like these, scientists have studied only synthetic MGF.^[2]

 

Mechanism of Action

Researchers have posited that MGF may promote muscle cell hypertrophy and repair, but via mechanisms that may differ compared to native IGF-1. IGF-I itself is posited to bind to the IGF-1 receptor on muscle cells and triggers the PI3K–Akt pathway, a signaling route that often promotes cell survival, differentiation, and controlled proliferation. In contrast, several in vitro studies have noted that synthetic MGF does not appear to activate Akt robustly. Instead, they may increase phosphorylation of ERK (particularly ERK5) and support MEF2C activity—two components more strongly linked to gene transcription events that may drive an increase in cellular size, aka hypertrophy.^[1][2] In other words, researchers posit that synthetic MGF seemingly steers the cell toward a gene expression profile that bolsters muscle cell growth in ways that might not precisely mirror the mature IGF-1 response.

 

Scientific Research and Studies

 

MGF and Muscle Cell Survival

Muscle cell damage is typically associated with increased oxidation levels, cellular death, and replacement with fibrotic tissue. A study indicates that MGF appears to reduce fibrosis in injured skeletal muscle cells, possibly by decreasing the synthesis of collagen types I and III.^[3] This reduction in collagen deposition might be mediated by the downregulation of pro-fibrotic cytokines such as TGF-β, which is thought to play a central role in fibrosis. Additionally, MGF may modulate the inflammatory environment within the injured muscle cells. MGF was associated with lowered levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ, suggesting that MGF might help attenuate excessive inflammatory responses that might otherwise impair recovery of muscular tissue. Furthermore, MGF potentially affects oxidative stress within the injured tissue. The study found that MGF led to a decrease in the expression of gp91phox, a key subunit of NADPH oxidases involved in the production of reactive oxygen species (ROS). By reducing oxidative stress, MGF may create a more favorable environment for muscle cell survival and tissue repair. Additionally, MGF might influence extracellular matrix (ECM) remodeling by modulating the expression of matrix metalloproteinases (MMPs). MGF was associated with altered levels of various MMPs, which are involved in the degradation and remodeling of the ECM. This modulation of MMP activity may contribute to a balanced ECM environment, facilitating muscular tissue recovery and mitigating excessive fibrosis.

 

MGF and Muscle Cell Development

It is posited that MGF might support the activation and proliferation of satellite cells, which are essential for the growth and repair of muscular tissue.^[4] By potentially delaying the onset of replicative senescence, MGF may extend the proliferative lifespan of these precursor cells. This delay in senescence may be mediated through the regulation of cell cycle proteins or by modulating stress response pathways, such as the p16 pathway, which scientists believe may have some impact on cell cycle arrest. Additionally, MGF appears to promote the fusion of myoblasts into myotubes, leading to hypertrophy. This hypertrophic potential might be achieved by recruiting reserve cells—those that typically remain quiescent and undifferentiated—to participate in myotube formation. By reducing the population of reserve cells, MGF may facilitate an increase in the number of nuclei per myotube. It might even support the synthesis of contractile proteins like myosin heavy chain (MyHC). These actions suggest that MGF might play a role in optimizing the balance between cell proliferation and differentiation, thereby supporting muscular tissue maintenance and adaptation.

 

MGF and Cardiac Cell Survival

MGF has been posited to exert anti-apoptotic potential and facilitate the recruitment of stem cells, which are crucial for cardiac tissue repair.^[5] One proposed mechanism is MGF’s ability to inhibit apoptosis in cardiac myocytes. The research indicates that MGF may reduce cell death in myocytes subjected to hypoxic conditions. This protective potential appears to be associated with an increase in Bcl-2 gene expression, a protein suggested to play a role in mitigating apoptosis. The study suggests that MGF might support cell survival by modulating apoptotic pathways, potentially through the upregulation of anti-apoptotic factors like Bcl-2.

MGF is thought to be potentially involved in the recruitment and migration of stem cells to the site of cardiac cell injury. The encapsulated MGF within the microrods was observed to increase the migration of mesenchymal stem cells (hMSCs) in vitro. This chemotactic activity of MGF may create a favorable microenvironment for stem cell homing, which is essential for tissue regeneration and repair. The mechanism behind this may involve MGF interacting with the IGF-1 receptor and activating downstream signaling pathways such as Erk1/2, which are implicated in cell migration and survival.

 

MGF and Muscular Tissue Fiber Thickness

Researchers have commented that full-length MGF may have “resulted in a 25% increase in the mean muscle fiber cross-sectional area” in experimental settings.^[6] The researchers posit that full-length MGF might engage similar signaling pathways as IGF-I, which is believed to coordinate myoblast proliferation, differentiation, and fiber formation in muscular tissue. The comparable maximal activation of IGF-IR by MGF at high concentrations indicates that, under certain conditions, MGF may potentially interact with the growth of muscular tissue akin to IGF-I. Additionally, full-length MGF was found to activate the insulin receptors IR-A and IR-B. The activation of IR-A by MGF reached levels similar to those induced by insulin at high concentrations, while IR-B stimulation by MGF was even more pronounced. This dual receptor activation posits that MGF may influence multiple signaling cascades involved in hypertrophy and repair of muscular tissue. The hypothetically better-supported stimulation of IR-B suggests a possible role for MGF in modulating metabolic and growth-related pathways that contribute to increased fiber size in muscular tissue. However, the truncated version of MGF may not have a similar potential

 

MGF and Bone Cell Proliferation

In experimental models involving bone defects, MGF was apparently associated with accelerated healing, which might be attributed to its potential to promote osteoblast activity and proliferation. This accelerated healing might result from better-supported cellular processes that support bone regeneration and remodeling. The potential mechanisms by which MGF influences bone cells and tissues appear to involve several intricate cellular pathways.

Primarily, MGF is believed to support the proliferation of osteoblast-like cells, as supported by data collected by observing the cells and their hypothesized ability to increase cell growth more than IGF-1. However, the researchers also noted that the “peptide actions were independent of IGF-IR signaling,” suggesting an alternative proliferative potential. This pro-proliferative potential might be mediated through the modulation of the cell cycle, where MGF possibly induces an accumulation of cells in the S and G2/M phases. Such cell cycle alterations suggest that MGF may even facilitate DNA synthesis and promote entry into mitosis, which may hypothetically support increased cell division.

 

MGF and Cartilage Cells

Some researchers suggest that MGF might regulate chondrocyte proliferation and migration.^[7] Studies indicate that MGF may support the mobility of mesenchymal stem cells (MSCs) and chondrocytes, possibly facilitating their recruitment to injury sites. This migration may be mediated through the activation of the RhoA/Yes-associated protein (YAP) signaling pathway, which is involved in cytoskeletal reorganization and cell movement. By promoting focal adhesion formation and cytoskeleton stability, MGF may help chondrocytes navigate the damaged environment to participate in tissue repair.

Additionally, MGF may influence chondrocyte differentiation and extracellular matrix (ECM) production. In the presence of transforming growth factor-beta 3 (TGF-β3), MGF appears to accelerate the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes, potentially supporting the synthesis of type II collagen (Col2) and aggrecan, key components of the cartilage ECM. This action might be linked to the activation of the extracellular signal-regulated kinase (ERK) pathway, which is associated with cellular differentiation processes.

MGF also appears to play some kind of role in modulating inflammatory responses and apoptosis within cartilage tissue. It may reduce the expression of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), thereby potentially alleviating inflammation-induced cartilage degradation. Furthermore, MGF might inhibit apoptotic pathways by downregulating proteins like Bax and caspase-3 while upregulating Bcl-2, which may help preserve chondrocyte viability in stressful environments. The interaction of MGF with signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and ERK/MAPK suggests it may help maintain cartilage homeostasis by promoting ECM synthesis and inhibiting catabolic processes.

The exact outcomes of these pathway activations appear to be context-dependent, varying between normal and damaged cartilage conditions. For instance, while PI3K/Akt signaling is generally associated with anabolic activities in functional cartilage, its role in damaged tissue is believed to potentially involve complex regulatory actions that are not yet fully understood. Moreover, MGF’s ability to induce the unfolded protein response (UPR) through pathways like protein kinase RNA-like ER kinase (PERK) indicates a potential role in managing cellular stress within chondrocytes. By influencing UPR-related proteins such as glucose-regulated protein 78 (GRP78), MGF may help chondrocytes adapt to hypoxic or mechanically stressful environments, thereby supporting their survival and function.

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. Li C, Vu K, Hazelgrove K, Kuemmerle JF. Increased IGF-IEc expression and mechano-growth factor production in intestinal muscle of fibrostenotic Crohn’s disease and smooth muscle hypertrophy. Am J Physiol Gastrointest Liver Physiol. 2015 Dec 1;309(11):G888-99. doi: 10.1152/ajpgi.00414.2014. Epub 2015 Oct 1. PMID: 26428636; PMCID: PMC4669353.
2. Matheny RW Jr, Nindl BC, Adamo ML. Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology. 2010 Mar;151(3):865-75. doi: 10.1210/en.2009-1217. Epub 2010 Feb 3. PMID: 20130113; PMCID: PMC2840678.
3. Liu X, Zeng Z, Zhao L, Chen P, Xiao W. Impaired Skeletal Muscle Regeneration Induced by Macrophage Depletion Could Be Partly Ameliorated by MGF Injection. Front Physiol. 2019 May 17;10:601. doi: 10.3389/fphys.2019.00601. PMID: 31164836; PMCID: PMC6534059.
4. Kandalla PK, Goldspink G, Butler-Browne G, Mouly V. Mechano Growth Factor E peptide (MGF-E), derived from an isoform of IGF-1, activates human muscle progenitor cells and induces an increase in their fusion potential at different ages. Mech Ageing Dev. 2011 Apr;132(4):154-62. doi: 10.1016/j.mad.2011.02.007. Epub 2011 Feb 25. PMID: 21354439.
5. Doroudian G, Pinney J, Ayala P, Los T, Desai TA, Russell B. Sustained delivery of MGF peptide from microrods attracts stem cells and reduces apoptosis of myocytes. Biomed Microdevices. 2014 Oct;16(5):705-15. doi: 10.1007/s10544-014-9875-z. PMID: 24908137; PMCID: PMC4418932.
6. Janssen JA, Hofland LJ, Strasburger CJ, van den Dungen ES, Thevis M. Potency of Full-Length MGF to Induce Maximal Activation of the IGF-I R Is Similar to Recombinant Human IGF-I at High Equimolar Concentrations. PLoS One. 2016 Mar 18;11(3):e0150453. doi: 10.1371/journal.pone.0150453. PMID: 26991004; PMCID: PMC4798685.
7. Liu Y, Duan M, Zhang D, Xie J. The role of mechano growth factor in chondrocytes and cartilage defects: a concise review. Acta Biochim Biophys Sin (Shanghai). 2023 May 12;55(5):701-712. doi: 10.3724/abbs.2023086. PMID: 37171185; PMCID: PMC10281885.

Adipotide, also referred to as FTPP or Prohibitin-targeting peptide 1 (Prohibitin-TP01), is a synthetic compound that may mimic specific parts of endogenously occurring proteins. In other words, it is posited to be a “peptidomimetic,” which means it may produce sequences of amino acids to imitate the way certain proteins normally work. The sequence of the peptide is GKGGRAKDC-GG-D(KLAKLAK)2. While scientific understanding is still incomplete, researchers posit that Adipotide’s unique nine-amino-acid segment (CKGGRAKDC) may be drawn to a receptor system involving two proteins, annexin A2 (ANXA2) and prohibitin (PHB).^[1]

Scientists believe that these two proteins function primarily as targets that help direct the Adipotide molecule to specific cells. Specifically, each of them appears to be present in different cells. Still, they are posited to form a unique ANXA2-PHB receptor system only found in white fat tissue, thus allowing for precise targeting.^[2] The remaining segment (KLAKLAK)₂ is believed to interfere with the function of mitochondria—the energy-producing parts of cells. Adipotide is posited to impede their function, leading to cell death. Early studies suggest that Adipotide FTPP may act mostly on white adipose tissue (WAT) cells, but the broader implications remain areas of ongoing research.

 

Mechanism of Action

ANXA2 and PHB are often found on endothelial cells in blood vessels connected to cells like fat cells (adipocyte-like cells) grown under laboratory conditions. Although the exact mechanisms are not fully understood, one component of Adipotide FTPP, also referred to by researchers as the CKGGRAKDC motif, may bind to these receptor complexes. After the peptide is taken up into the cell, another segment—called the (KLAKLAK)₂ domain—may compromise the integrity of the membranes of the mitochondria of endocrine cells, which may trigger processes leading to cell death (apoptosis). This process is posited to lead to the reduction or destruction of the adipose vasculature, which in turn might influence the local adipose microenvironment.

Through this process, researchers believe that Adipotide FTPP may contribute to some level of reduction in the vascular network that nourishes white adipose tissue, ultimately resulting in diminished adipose mass.^[3] Furthermore, the binding of the peptide to the receptors might influence the positioning and activity of proteins involved in transporting fatty acids, such as CD36, potentially affecting how these cells take in and process fats. Specifically, researchers posit that a “biochemical interaction between ANX2 and PHB regulates CD36-mediated fatty acid transport in WAT, thus revealing a new potential pathway for intervention in metabolic diseases.”^[4] Thus, by interfering with the normal partnership between ANXA2 and PHB, Adipotide FTPP might reduce the efficiency with which fatty acids enter adipocyte-like cells.

 

Scientific Research and Studies

 

Adipotide FTPP and Fat Cells Metabolism

Laboratory investigations in different models indicate that targeting the vascular supply may induce notable reductions in white adipose mass.^[5] Over a few weeks of experimentation, the researchers were able to produce imaging-based assessments such as DEXA scanning and MRI and have apparently observed a total adiposity reduction of approximately 38.7%, including localized decreases that may range from around 17.5% to 27.0%. Such changes may be related to a diminished capillary network that potentially limits nutrient and oxygen delivery to adipose compartments. This may hinder the survival and maintenance of cells like these.

Early evaluations further suggest that shifts in metabolic parameters might accompany these vascular alterations. It remains unclear whether these outcomes arise directly from the reduced vascular supply or from more complex signaling feedback originating within the disrupted adipose milieu, where metabolic intermediaries or hormonal cues might adjust in response to the altered environment. The researchers also commented that the apparent “weight loss is also accompanied by a modest reduction in serum-free fatty acids and an improvement in insulin resistance.”

 

Adipotide FTPP and Energy Intake

In controlled laboratory settings, murine models exposed to Adipotide FTPP apparently displayed considerable fat mass reduction when on high-fat diets. Still, the same was not true for murine research models on low-fat diets.^[6] This difference may be related to the expanded adipose compartment in high-fat–fed models, which possibly provides a more substantial vascular target. Moreover, during several days of exposure to Adipotide FTPP directed at white adipose vasculature, observation of these research models indicated a progressive decrease in caloric intake that was not immediately obvious at the initiation of the experimentation but occurred after some delay.

Such a delay in reduced consumption may indicate that the targeted apoptotic process requires some time to influence downstream metabolic or behavioral signals. Although leptin levels, typically associated with suppression of hunger hormone signals, appeared reduced along with fat mass, the researchers posit that the diminished nutrient supply and possible adipose-derived signals might have overridden the usual compensatory hyperphagic response expected from lower circulating leptin.

 

Adipotide FTPP and Insulin Resistance Models

Through the destruction of these vascular cells, there is potentially a reduction in nutrient and oxygen delivery to the adipose tissue itself, which may lead to fewer and possibly smaller adipocytes. Researchers suggest that this vascular targeting apparently results in reprogramming of metabolic pathways, as indicated by altered expression profiles of genes involved in mitochondrial processes, oxidative phosphorylation, and branched-chain amino acid degradation.^[7] Such transcriptional shifts may potentially restore or at least partly normalize adipose tissue function that had been disrupted in the context of excess adiposity. In controlled laboratory work with murine models, the peptide’s influence on circulating lipids and metabolites suggests that it may decrease reliance on fatty acid oxidation and instead promote glucose utilization.

Altered levels of various metabolites, including a range of fatty acids and acylcarnitines, might reflect a metabolic state more conducive to better-supported glucose regulation. Although the exact details remain uncertain, the peptide may restore a more favorable metabolic profile within adipose tissue. Something like this may potentially contribute to the reversal of some of the mitochondrial and metabolic impairments that develop during exposure to high-fat conditions. At the same time, the peptide’s potential influence on macrophage-related gene expression hints at subtle immunological shifts in the adipose environment, though the implications for these changes remain unclear.

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References:

1. Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004 Jun;10(6):625-32. doi: 10.1038/nm1048. Epub 2004 May 9. PMID: 15133506.
2. Staquicini FI, Cardó-Vila M, Kolonin MG, Trepel M, Edwards JK, Nunes DN, Sergeeva A, Efstathiou E, Sun J, Almeida NF, Tu SM, Botz GH, Wallace MJ, O’Connell DJ, Krajewski S, Gershenwald JE, Molldrem JJ, Flamm AL, Koivunen E, Pentz RD, Dias-Neto E, Setubal JC, Cahill DJ, Troncoso P, Do KA, Logothetis CJ, Sidman RL, Pasqualini R, Arap W. Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18637-42. doi: 10.1073/pnas.1114503108. Epub 2011 Nov 2. PMID: 22049339; PMCID: PMC3219136.
3. Hossen N, Kajimoto K, Akita H, Hyodo M, Harashima H. A comparative study between nanoparticle-targeted therapeutics and bioconjugates as obesity medication. J Control Release. 2013 Oct 28;171(2):104-12. doi: 10.1016/j.jconrel.2013.07.013. Epub 2013 Jul 18. PMID: 23871959.
4. Salameh A, Daquinag AC, Staquicini DI, An Z, Hajjar KA, Pasqualini R, Arap W, Kolonin MG. Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight. 2016 Jul 7;1(10):e86351. doi: 10.1172/jci.insight.86351. PMID: 27468426; PMCID: PMC4959783.
5. Barnhart KF, Christianson DR, Hanley PW, Driessen WH, Bernacky BJ, Baze WB, Wen S, Tian M, Ma J, Kolonin MG, Saha PK, Do KA, Hulvat JF, Gelovani JG, Chan L, Arap W, Pasqualini R. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med. 2011 Nov 9;3(108):108ra112. doi: 10.Doi6/scitranslmed.3002621. PMID: 22072637; PMCID: PMC3666164.
6. Kim DH, Woods SC, Seeley RJ. Peptide is designed to elicit apoptosis in adipose tissue endothelium and reduce food intake and body weight. Diabetes. 2010 Apr;59(4):907-15. doi: 10.2337/db09-1141. Epub 2010 Jan 26. PMID: 20103704; PMCID: PMC2844838.
7. Kim DH, Sartor MA, Bain JR, Sandoval D, Stevens RD, Medvedovic M, Newgard CB, Woods SC, Seeley RJ. Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium. Diabetes. 2012 Sep;61(9):2299-310. doi: 10.2337/db11-1579. Epub 2012 Jun 25. PMID: 22733798; PMCID: PMC3425411.