Pegylated Mechano-growth factor (PEG-MGF) Research

Pegylation is a process of attaching polyethylene glycol to another chemical compound. It is often done to reduce the body’s natural immune reaction to an agent or, as in the case of PEG-MGF, to increase the half-life of the compound in the blood by reducing clearance in the kidneys. Pegylation is common, safe, and has a number of advantages. PEG-MGF was developed because MGF has a very short half-life in blood. Though it persists for longer periods of time in muscle tissue, MGF administered exogenously has a short half-life because it passes through the blood stream first unless it is injected directly into muscle tissue. PEG-MGF helps to offset this particular disadvantage.

PEG-MGF and Skeletal Muscle

Injuries to muscle are common in sports and include everything from strains and sprains to outright avulsion injuries. In many cases, these types of injury require surgical repair. Regardless of the treatment, however, recover tends to be long and results are not always perfect. Research in a mouse model of muscle injury, however, suggests that MGF injected directly into muscle protects the cells by decreasing expression of certain inflammatory hormones, and reducing oxidative stress^[1].

Similar research by Sun et. al. shows that MGF modulates muscle inflammation and improves the recruitment of macrophages and neutrophils to the site of injury^[2]. Both studies are based on the previous knowledge that exercise-induced muscle damage stimulates the release of IGF-1Ea and IGF-1Eb, both of which are closely related to MGF^[3].

Studies carried out by an international group of endocrinology researchers reveals that MGF stimulates the insulin-like growth factor 1 receptor just as much as IGF-1^[4]. Stimulation of this receptor has been linked to decreased aging, increased lean body mass, and improved energy homeostasis in humans. This function suggests that PEG-MGF can produce effects similar to IGF-1 leading to improved muscle repair, enhanced fat metabolism, and overall increases in lean body mass.

Research in mice also shows a 25% increase in mean muscle fiber size when MGF is administered to mice that are exercising^[5]. In this study, the MGF was injected directly into the muscle, something that authors Goldspink and Jakeman point out as a serious limitation as the protein would have to be injected into every muscle in which hypertrophy is to be optimized. PEG-MGF solves this particular problem by increasing the plasma half-life of MGF and allowing it to be administered via a single intravenous injection rather than multiple intramuscular injections.

PEG-MGF Research in Heart Muscle Repair

Research carried out in the department of bioengineering at the University of Illinois shows that MGF inhibits the programmed cell death that cardiac muscle cells undergo following hypoxia. Furthermore, the peptide appears to recruit cardiac stem cells to the site of injury and may therefore help in regeneration and healing following heart attack. Rats in the study were administered MGF within eight hours of hypoxia and showed less cell death and greater stem cell recruitment compared to controls that did not receive MGF^[6]. Dr. Doroudian, lead author of the research, believes that using nanorods to deliver MDF in the setting of heart damage may be an effective way to provide localized, long-term therapy of the bioactive peptide to areas of injury.

Similar research indicates that localized delivery of MGF shows that it can improve cardiac function following heart attack by reducing pathologic hypertrophy. Rats in the study that were treated with PEG-MGF showed better hemodynamics and less cardiac remodeling than untreated rats^[7]. Carpenter et. al. have similarly shown that MGF injected in the setting of acute myocardial infarction can reduce cardiomyocyte injury by as much as 35%.

Bone Repair and Growth

Research in rabbits indicates that PEG-MGF can increase the rate of bone repair by boosting the proliferation of osteoblasts, the cells that mineralize bone. Rabbits treated with high doses of MGF showed the same level of healing at four weeks that was seen in controls at six weeks^[8]. There is hope that this technique can help scientists learn how to promote bone healing and reduce time that people must spend immobilized to allow for healing.

Protecting Cartilage

Research indicates that MGF can improve the function of chondrocytes, the cells primarily responsible for cartilage health and deposition. Research in mice shows that MGF enhances the migration of chondrocytes from bone, where the cells develop, into cartilage where they have an effect^[9]. This is a perfect setting for PEG-MGF because it could be injected into compromised joint spaces and would remain for long periods of time. A single injection could, in theory, be useful for weeks or even months whereas standard MGF has an effect limited to minutes or perhaps hours.

Dental Applications

Research in cell cultures of human periodontal ligament cells indicates that PEG-MGF can improve osteogenic differentiation and boost expression of MMP-1 and MMP-2^[10]. These factors act to improve repair of the ligaments that attach the tooth to bone and may offer an alternative to too extractions and implants, allowing people to keep their natural teeth after injury. There is even speculation that PEG-MGF may make it possible to save damaged or avulsed teeth after they are surgically re-implanted.

Potential Neuroprotective Effects

Alexander Walker, Editorial Assistant at BioMed Central, has recently reviewed a study exploring the long-term effects of increased levels of MGF in the brain and central nervous system. The study reveals that higher levels of MGF help to reduce the effects of age-related neuron degeneration, resulting in mice that retain their cognitive functions and operate a peak cognitive performance longer into old age. According to Walker, “the efficacy of MGF in the brain is age-dependent” as mice in the study had improved results both initially and over the long-term if MGF overexpression occurred earlier in life^[11].

Treatment with MGF has also been shown to improve muscle weakness and reduce the loss of motor-neurons in mouse models of ALS^[12]. According to Dluzniewska et al., MGF is naturally expressed in the brain following hypoxic injury and is over-expressed in regions of the brain where neuron regeneration is greatest. By administering exogenous MGF, it may be possible to reduce the impact of a number of neurological diseases, not by addressing the root cause of the condition, but by preventing the death of neurons in the brain and spinal cord despite the ongoing disease process.

References

• [1] X. Liu, Z. Zeng, L. Zhao, P. Chen, and W. Xiao, “Impaired Skeletal Muscle Regeneration Induced by Macrophage Depletion Could Be Partly Ameliorated by MGF Injection,” Front. Physiol., vol. 10, p. 601, 2019. [PubMed]
• [2] K.-T. Sun, K.-K. Cheung, S. W. N. Au, S. S. Yeung, and E. W. Yeung, “Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury,” Front. Physiol., vol. 9, 2018. [PMC]
• [3] A. Philippou et al., “Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: characterization of the MGF E peptide actions in vitro,” Vivo Athens Greece, vol. 23, no. 4, pp. 567–575, Aug. 2009. [PubMed]
• [4] J. A. M. J. L. Janssen, L. J. Hofland, C. J. Strasburger, E. S. R. van den Dungen, and M. Thevis, “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, vol. 11, no. 3, Mar. 2016. [PLoS ONE]
• [5] G. Goldspink, “Research on mechano growth factor: its potential for optimising physical training as well as misuse in doping,” Br. J. Sports Med., vol. 39, no. 11, pp. 787–788, Nov. 2005. [BMJ Journals]
• [6] G. Doroudian, J. Pinney, P. Ayala, T. Los, T. A. Desai, and B. Russell, “Sustained delivery of MGF peptide from microrods attracts stem cells and reduces apoptosis of myocytes,” Biomed. Microdevices, vol. 16, no. 5, pp. 705–715, Oct. 2014. [PubMed]
• 7] J. R. Peña, J. R. Pinney, P. Ayala, T. A. Desai, and P. H. Goldspink, “Localized delivery of mechano-growth factor E-domain peptide via polymeric microstructures improves cardiac function following myocardial infarction,” Biomaterials, vol. 46, pp. 26–34, Apr. 2015. [PubMed]
• [8] M. Deng et al., “Mechano growth factor E peptide promotes osteoblasts proliferation and bone-defect healing in rabbits,” Int. Orthop., vol. 35, no. 7, pp. 1099–1106, Jul. 2011. [PubMed]
• [9] X. Jing et al., “Mechano-growth factor protects against mechanical overload induced damage and promotes migration of growth plate chondrocytes through RhoA/YAP pathway,” Exp. Cell Res., vol. 366, no. 2, pp. 81–91, May 2018. [PubMed]
• [10] J.-T. Chen, Y. Wang, Z.-F. Zhou, and K.-W. Wei, “[Mechano-growth factor regulated cyclic stretch-induced osteogenic differentiation and MMP-1, MMP-2 expression in human periodontal ligament cells by activating the MEK/ERK1/2 pathway],” Shanghai Kou Qiang Yi Xue Shanghai J. Stomatol., vol. 28, no. 1, pp. 6–12, Feb. 2019. [PubMed]
• [11] A. W. graduated from the U. of L. with a Bs. in Z. in 2015 H. joined B. C. as E. A. for the L. S. department in May 2017, I. P. I. in Parasitology, entomology, and E. Biology, “Hearts and Minds of Mice and Men: Mechano Growth Factor a new tool in the battle against age-related neuron loss?,” On Biology, 20-Jul-2017. [Online]. Available: https://blogs.biomedcentral.com/on-biology/2017/07/20/hearts-minds-mice-men-mechano-growth-factor-new-tool-battle-age-related-neuron-loss/. [Accessed: 30-Jun-2019].
• [12] J. Dluzniewska et al., “A strong neuroprotective effect of the autonomous C-terminal peptide of IGF-1 Ec (MGF) in brain ischemia,” FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., vol. 19, no. 13, pp. 1896–1898, Nov. 2005. [PubMed]