MGF stands for "mechano growth factor." It isn't a separate hormone - it's a different-shaped version of IGF-1, the growth signal your body already makes, that shows up specifically when muscle, bone, cartilage, or nerve tissue gets stressed or damaged. Researchers discovered it while studying how animal muscle responds to exercise and injury, and since then almost all the work on it has stayed in petri dishes and animal models. A synthetic 24-amino-acid snippet of MGF is sold online as a "recovery peptide," popular in bodybuilding and biohacking circles, but that popularity runs well ahead of the science - there are no completed human trials of the injected peptide, and one of the more careful lab studies couldn't even reproduce its basic effect on muscle cells.
How strong is the evidence?
Every study that actually gave real MGF peptide to a living subject and measured an effect was done in rats, mice, or rabbits - never in a human clinical trial. The human-related studies in this file are either tissue-biopsy surveys (measuring how much natural MGF a person's muscle, cancer, or endometrial tissue makes on its own) or lab-dish experiments using human cells - not people injecting the peptide. Making things murkier, a careful 2014 study run independently by two pharmaceutical companies could not reproduce the muscle-cell effects that made MGF popular in the first place. That combination - animal/lab-only dosing data plus a notable failed replication - is why this page is graded preclinical with low confidence.
Uses
What people use it for
Muscle recovery after hard training (marketed use)
TheoryThis is the number one reason people buy MGF as a research peptide - hoping it speeds up repair after intense workouts. The idea comes from real biology (muscle does make more of this IGF-1 variant after being stressed or damaged), but nobody has tested whether injecting a synthetic piece of it actually improves recovery in a real, training person.
Joint, tendon, and bone injury research
Animal / labIn labs, synthetic MGF peptide has been tested on damaged cartilage, injured tendons, and bone fractures in animals and cell cultures, to see if it can help those tissues rebuild faster.
Anti-aging and brain-health interest (marketed use)
TheorySome sellers pitch MGF for slowing age-related muscle and brain decline, based on mouse studies showing it can boost new brain cell growth and protect nerves. This is a speculative use extrapolated from animal data, not a demonstrated human benefit.
Cancer biology research (lab use only, not a therapy)
Animal / labIronically, some of the deepest research on this molecule isn't about performance at all - scientists study it to understand how prostate, breast, endometrial, and colon cancers hijack the same repair signal to grow and spread. This is purely a research tool in that context, not something anyone should take.
Potential benefits
What it may help with
May switch on muscle repair cells - in a dish, from human donors
Some human dataWhen researchers applied synthetic MGF peptide to muscle stem cells taken from people, it kept younger donors' cells dividing longer and helped them fuse together, hinting at a role in patching up muscle. But a separate, more rigorous industry study could not reproduce any effect on muscle cell growth even at high doses, so this claimed benefit is genuinely contested, not settled.
May speed tendon and bone healing - in animals
Animal / labRats treated with MGF peptide directly at an injured Achilles tendon healed with stronger, better-organized tissue than untreated rats. Rabbits given peptide injections after bone-defect surgery also healed more completely at the higher of two doses tested.
May help protect cartilage after joint injury - in animals and lab cells
Animal / labIn rat joint-injury models and cartilage cell experiments, the peptide helped cartilage cells survive low-oxygen stress, kept producing the collagen that cushions joints, and reduced arthritis-like tissue damage. It's an early signal for conditions like osteoarthritis, not a proven treatment.
May calm inflammation around wounds and implants
Animal / labCoating a wound-healing material with MGF nudged immune cells (macrophages) toward a calmer, tissue-repairing mode in rats, reducing the scar-like "foreign body" reaction the body normally mounts against implanted material.
Studies:33732968May protect nerve cells and support brain aging - in mice
Animal / labIn aging mice, extra MGF increased the birth of new brain cells and helped preserve their sense of smell. Separate mouse studies found it protected nerve cells from chemotherapy-drug damage and improved muscle strength and nerve survival in a model of ALS (Lou Gehrig's disease). All of this is in mice, not people.
What to watch for
Side effects & risks
- Serious
May encourage cancer growth signals
Multiple lab and tissue studies show that IGF-1Ec/MGF - and the fragment it produces, called PEc - is turned up in prostate, breast, endometrial, and colorectal cancer tissue, and exposing cancer cells to synthetic MGF peptide made them grow, spread, and migrate more. Anyone with a personal or strong family history of cancer should treat this as a real concern, not background noise.
- Moderate
Heart function changes seen in animal dosing
In mice given the peptide daily for two weeks, both a low and a high dose slightly weakened heart pumping function, while a middle dose had the opposite effect - a sign the dose-response relationship is unpredictable and not something to guess at.
- Mild
Mixed, sometimes opposite effects on bone cells
One study found the peptide helped bone-forming cells multiply and healed bone defects in rabbits, while another found the same peptide blocked those cells from maturing and depositing calcium. The real-world net effect on bone isn't settled.
- Moderate
No real-world human safety record
Because MGF peptide has never gone through a human clinical trial, there is no formal record of side effects in people - allergic reactions, injection-site problems, and long-term risks are simply unknown and unmonitored.
Dosing
Dosing — what studies used
There is no established human dose for MGF, because it has never been tested in a human clinical trial. Any amount, frequency, or injection schedule you see online is not based on science done in people - it's either guesswork or borrowed loosely from animal studies. The doses below are what researchers used in rats, rabbits, and mice; they are not a recommendation for a person.
Rat Achilles tendon injury
Animal study1000 ng/ml applied at the injury site
Not specified as repeat dosing in the abstract · Healing period tracked over several weeks · Local application/injection at the injured tendon
Improved tendon strength and tissue organization versus saline in rats; not tested in people.
Rabbit bone-defect (fracture) healing
Animal study28.5 or 57 micrograms per kilogram of body weight
Once daily · 5 consecutive days after surgery · Injection
Only the higher (57 mcg/kg) dose produced significantly better bone healing than no treatment.
Mouse cardiac function study
Animal study2.25, 4.5, or 9 milligrams per kilogram of body weight per day
Daily · 2 weeks · Injection
Different doses had different, sometimes opposite, effects on heart function - the low and high doses weakened heart contraction while the middle dose did not, underscoring that this isn't a simple 'more is better' peptide.
MGF sold online is an unregulated research chemical, not a pharmaceutical product - purity and actual contents of any given vial are not verified by any of the studies in this file.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Think of IGF-1 as a growth-and-repair signal your body sends out, mostly made by the liver and carried in the blood. MGF is a locally-made variant of that same signal - your muscle, bone, or nerve tissue makes it right at the spot where it's stressed or injured, instead of relying on the signal traveling in from the liver. In theory, its job is to wake up dormant repair cells (called satellite cells in muscle) so they can help rebuild damaged tissue. The products sold as "MGF" are a small synthetic snippet - just the last 24 building blocks - of this natural molecule. Studies show this snippet often works through a different route than regular IGF-1: it can activate a cell-growth switch called ERK without touching the other main growth pathway (Akt), and several experiments found it works even when the usual IGF-1 receptor is blocked. That's scientifically interesting, but it also means the synthetic snippet may not behave the way marketing claims - and one careful lab replication found it did nothing at all to muscle cells.
Who should avoid it
- Personal or strong family history of cancer, especially prostate, breast, endometrial, or colorectal cancer - lab studies repeatedly link this molecule to cancer cell growth and spread.
- Pregnancy or breastfeeding - no safety data exists.
- Anyone expecting a proven medical treatment for muscle building or injury recovery - no human evidence supports that use yet.
- Anyone unable to verify what's actually in the vial - this is sold as an unregulated research chemical, not a tested drug.
Interactions to know
- No documented drug interactions - it has not been formally studied alongside medications or supplements.
- Because its signaling overlaps with insulin and IGF-1 pathways, combining it with insulin, growth hormone, or other IGF-1-boosting products without medical supervision adds unknown risk.
The papers that matter most
Key studies
Two pharmaceutical companies independently tried to reproduce MGF's famous muscle-cell effects and found nothing - no increase in proliferation, no change in differentiation - at doses up to 500 ng/ml, in both mouse and human muscle cells. This is the single most important reality-check paper in the file.
Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells.
A widely cited review that openly states no natural MGF peptide has ever actually been isolated from living tissue, blood, or cell culture medium - everything studied is a synthetic stand-in, not a confirmed real-world molecule.
Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration.
The main positive evidence behind the muscle-recovery pitch: synthetic MGF peptide extended the life and improved fusion of muscle stem cells taken from younger human donors, but not from older donors.
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.
In a rat osteoarthritis model, the peptide reduced cartilage damage and supported cartilage-building cells - one of the stronger tissue-protection signals in the file, though still animal-only.
Pretreatment with mechano growth factor E peptide attenuates osteoarthritis through improving cell proliferation and extracellular matrix synthesis in chondrocytes under severe hypoxia.
One of the few studies with an actual dose-response test in a live animal: daily injections after a bone-defect surgery improved healing, but only at the higher of two doses tried.
Mechano growth factor E peptide promotes osteoblasts proliferation and bone-defect healing in rabbits.
Shows the same peptide fragment that's marketed for recovery actively drives prostate cancer cell growth, invasion, and metastasis in mice, and its levels track with tumor stage in human biopsies - the clearest safety-relevant finding in the file.
Oncogenic Role of the Ec Peptide of the IGF-1Ec Isoform in Prostate Cancer.
Bottom line
MGF is a real piece of biology - a local repair signal muscle makes after damage - but the injectable version sold online is still stuck at the animal-and-lab stage. No human trials exist, a serious industry replication attempt found it didn't work on muscle cells as advertised, and several studies tie the same molecule to cancer growth signals. Until real human trials appear, treat recovery claims as speculative and weigh the cancer-related findings seriously before considering it.
Research papers
Studies we have on file for MGF. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Biological activity of the e domain of the IGF-1Ec as addressed by synthetic peptides.
Insulin-like growth factor-1 (IGF-1) is a multipotent growth factor involved in the growth, development and regulation of homeostasis in a tissue-specific manner. Alternative splicing, multiple transcription initiation sites and different polyadelynation signals give rise to diverse mRNA isoforms, such as IGF-1Ea, IGF-1Eb and IGF-1Ec transcripts. There is increasing interest in the expression of the IGF-1 isoforms and their potential distinct biological role. IGF-1Ec results from alternative splicing of exons 4-5-6 and its expression is upregulated in various conditions and pathologies. Recent studies have shown that IGF-1Ec is preferentially increased after injury in skeletal muscle during post-infarctal myocardium remodelling and in cancer tissues and cell lines. A synthetic analogue corresponding to the last 24 aa of the E domain of the IGF-1Ec isoform has been used to elucidate its potential biological role. The aim of the present review is to describe and discuss the putative bioactivity of the E domain of the IGF-1Ec isoform.
Gene expression in skeletal muscle.
Muscle has an intrinsic ability to change its mass and phenotype in response to activity. This process involves quantitative and qualitative changes in gene expression, including that of the myosin heavy chain isogenes that encode different types of molecular motors. This, and the differential expression of metabolic genes, results in altered fatigue resistance and power output. The regulation of muscle mass involves autocrine as well as systemic factors. We have cloned the cDNAs of local and systemic isoforms of insulin-like growth factor-I (IGF-I) from exercised muscle. Although different isoforms are derived from the IGF-I gene by alternative splicing, the RNA transcript of one of them is only detectable following injury and/or mechanical activity. Thus this protein has been called mechano growth factor (MGF). Because of a reading-frame shift, MGF has a different 3' sequence and a different mode of action compared with systemic or liver IGF-I. Although MGF has been called a growth factor, it may be regulated as a local repair factor.
Preferential expression of IGF-1Ec (MGF) transcript in cancerous tissues of human prostate: evidence for a novel and autonomous growth factor activity of MGF E peptide in human prostate cancer cells.
By alternative splicing the IGF-1 gene produces several different transcripts, including IGF-1Ec (MGF). The latter has been mainly associated with muscle regeneration processes. We used immunohistochemistry, RT-PCR, and Western analysis to show the expression status of MGF in prostate tissue and human prostate cell lines (HPrEC, PC-3, and LNCaP) and we studied the exogenous administration of the MGF peptide E on cellular proliferation using trypan blue and MTT assays, before and after the silencing of the IGF-1 receptor and insulin receptor (siRNA methods). The MGF-induced intracellular activation was examined by Western analysis of the active forms of ERK1/2 and Akt. We documented that MGF is overexpressed in human prostate cancer (PCa) tissues and in human PC-3 and LNCaP cells. Notably, MGF expression was remarkably higher in PCa and prostatic intraepithelial neoplasia (PIN) than normal prostate tissues, while the normal prostate epithelial cells (HPrEC) did not express MGF. Exogenous administration of a synthetic MGF E peptide stimulated the PCa cell growth and activated ERK1/2 phosphorylation without affecting Akt phosphorylation. IGF-1R or insulin receptor (IR) silencing did not affect the mitogenic activity and intracellular signaling of the MGF E peptide in these PCa cells. These data suggest the possible implication of MGF E peptide in cancer biology, implying a preferential MGF expression in PCa tissues and cells. This preferential IGF-1 mRNA expression generates the MGF E peptide that possesses mitogenic activity through mechanisms independent of IGF-1R, IR, and hybrid IGF-1R/IR.
Insulinlike growth factor-1Ec (MGF) expression in eutopic and ectopic endometrium: characterization of the MGF E-peptide actions in vitro.
The transcription of the insulinlike growth factor 1 (igf-1) gene generates three mRNA isoforms, namely IGF-1Ea, IGF-1Eb and IGF-1Ec (or MGF [mechano growth factor]). Herein, we analyzed the expression of IGF-1 isoforms in eutopic and ectopic endometrium (red lesions and endometriotic cysts) of women with endometriosis, and we characterized the actions of a synthetic MGF E-peptide on KLE cells. Our data documented that all three igf-1 gene transcripts are expressed in the stromal cells of the eutopic and ectopic endometrium; however, endometriotic cysts contained significantly lower IGF-1 isoform expression, both at the mRNA and protein level, as was shown using semiquantitative PCR and immunohistochemical methods. In addition, the glandular cells of the eutopic endometrium did not express any of the IGF-1 isoforms; however, the glandular cells of the ectopic endometrium (red lesions) did express the IGF-1Ec at mRNA and protein level. Furthermore, synthetic MGF E-peptide, which comprised the last 24 amino acids of the MGF, stimulated the growth of the KLE cells. Experimental silencing of the type 1 IGF receptor (IGF-1R) and insulin receptor expression of KLE cells (siRNA knock-out methods) did not alter the mitogenic action of the synthetic MGF E-peptide, revealing that MGF E-peptide stimulates the growth of KLE cells via an IGF-1R-independent and insulin receptor-independent mechanism. These data suggest that the IGF-1Ec transcript might generate, apart from mature IGF-1 peptide, another posttranslational bioactive product that may have an important role in endometriosis pathophysiology.
Surface modification of electrospun fibers with mechano-growth factor for mitigating the foreign-body reaction.
The implantation of synthetic polymeric scaffolds induced foreign-body reaction (FBR) seriously influence the wound healing and impair functionality recovery. A novel short peptide, mechano-growth factor (MGF), was introduced in this study to modify an electrospun polycaprolactone (PCL) fibrous scaffold to direct the macrophage phenotype transition and mitigate the FBR. In vitro studies discovered the cell signal transduction mechanism of MGF regulates the macrophage polarization via the expression of related genes and proteins. We found that macrophages response the MGF stimuli via endocytosis, then MGF promotes the histone acetylation and upregulates the STAT6 expression to direct an anti-inflammatory phenotype transition. Subsequently, an immunoregulatory electrospun PCL fibrous scaffold was modified by silk fibroin (SF) single-component layer-by-layer assembly, and the SF was decorated with MGF via click chemistry. Macrophages seeded on scaffold to identify the function of MGF modified scaffold in directing macrophage polarization in vitro. Parallelly, rat subcutaneous implantation model and rat tendon adhesion model were performed to detect the immunomodulatory ability of the MGF-modified scaffold in vivo. The results demonstrate that MGF-modified scaffold is beneficial to the transformation of macrophages to M2 phenotype in vitro. More importantly, MGF-functionalized scaffold can inhibit the FBR at the subcutaneous tissue and prevent tissue adhesion.
Growth factors and muscle ageing.
Loss of muscle mass (sarcopenia) is one of the main problems associated with ageing as it has major health care as well as socioeconomic implications. The growth hormone (GH)/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I and that there are local as well as systemic forms of IGF-I which have different functions. At least two different kinds of IGF-I that are expressed by skeletal muscle are derived from the IGF-I gene by alternative splicing, one of which is expressed in response to physical activity which has now been called 'mechano growth factor' (MGF). The other is similar to the systemic or liver type (IGF-IEa) and is important as the provider of mature IGF-I required for upregulating protein synthesis. MGF differs from systemic IGF-IEa in that it has a different peptide sequence which is responsible for replenishing the satellite (stem) cells in skeletal muscle. The ability to produce MGF declines with age, and this is commensurate with the decline in circulating GH levels. GH treatment up regulates the level of IGF-I gene expression in older people and when combined with resistance exercise more is spliced towards MGF and hence should improve the ability of muscle to respond to physical activity. The possibility of ameliorating sarcopenia using MGF is discussed.
IL-6 is associated to IGF-1Ec upregulation and Ec peptide secretion, from prostate tumors.
Ec peptide (PEc), resulting from the proteolytic cleavage of the IGF-1Ec isoform, is involved in prostate cancer progression and metastasis, whereas in muscle tissue, it is associated with the mobilization of satellite cells prior to repair. Our aim is to determine the physiological conditions associated to the IGF-1Ec upregulation and PEc secretion in prostate tumors, as well as, the effect of tumor PEc on tumor repair. IGF-1 (mature and isoforms) expression was examined by qRT-PCR, both in prostate cancer cells co-incubated with cells of the immune response (IR) and in tumors. PEc secretion was determined by Multiple Reaction Monitoring. The effect of PEc, on mesenchymal stem cell (MSC) mobilization and repair, was examined using migration and invasion assays, FISH and immunohistochemistry (IHC). The JAK/STAT signaling pathway leading to the IGF1-Ec expression was examined by western blot analysis. Determination of the expression and localization of IL-6 and IGF-1Ec in prostate tumors was examined by qRT-PCR and by IHC. We documented that IL-6 secreted by IR cells activates the JAK2 and STAT3 pathway through IL-6 receptor in cancer cells, leading to the IGF-1Ec upregulation and PEc secretion, as well as to the IL-6 expression and secretion. The resulting PEc, apart from its oncogenic role, also mobilizes MSCs towards the tumor, thus promoting tumor repair. IL-6 leads to the PEc secretion from prostate cancer cells. Apart from its oncogenic role, PEc is also involved in the mobilization of MSCs resulting in tumor repair.
Pretreatment with mechano growth factor E peptide attenuates osteoarthritis through improving cell proliferation and extracellular matrix synthesis in chondrocytes under severe hypoxia.
Osteoarthritis (OA) is characterized by pain and declining gait function associated with degeneration of cartilage. A severe hypoxic environment occurs due to tissue injury in the joint cavity and may aggravate the development of OA. In this study, the effects of severe hypoxia and treatment with mechano growth factor (MGF) E peptide on metabolism of the extracellular matrix (ECM) during the progression of OA were determined. The results showed that cell viability, cell proliferation, and type II collagen expression in chondrocytes were significantly inhibited by cobalt chloride (CoCl2)-simulated severe hypoxia, whereas cell apoptosis and expression levels of hypoxia inducible factor 1 alpha, type I collagen, and matrix metalloproteinases 1/13 were clearly induced. Pretreatment with MGF E peptide reduced the abovementioned adverse effects induced by CoCl2-simulated severe hypoxia in chondrocytes. Pretreatment also upregulated the proliferation of chondrocytes under severe hypoxia through the PI3K-Akt and MEK-ERK1/2 signaling pathways. In a rat model of monosodium iodoacetate (MIA)-induced OA. MIA treatment induced tissue necrosis and cartilage degeneration, and histological score was significantly decreased. The levels of type II collagen and aggrecan were reduced after MIA treatment for 4 or 6 weeks, and abnormal distribution of ECM occurred in the inner epicondyle after 6 weeks. MGF E peptide also reduced the progression of MIA-induced OA by retarding cartilage degeneration, upregulating type II collagen synthesis, and improving ECM distribution after 4 or 6 weeks. Our findings suggest that MGF attenuates the progression of OA, and thus may be applied for the treatment of OA in the clinic.
Oncogenic Role of the Ec Peptide of the IGF-1Ec Isoform in Prostate Cancer.
IGF-1 is one of the key molecules in cancer biology; however, little is known about the role of the preferential expression of the premature IGF-1 isoforms in prostate cancer. We have examined the role of the cleaved COO- terminal peptide (PEc) of the third IGF-1 isoform, IGF-1Ec, in prostate cancer. Our evidence suggests that endogenously produced PEc induces cellular proliferation in the human prostate cancer cells (PC-3) in vitro and in vivo, by activating the ERK1/2 pathway in an autocrine/paracrine manner. PEc overexpressing cells and tumors presented evidence of epithelial to mesenchymal transition, whereas the orthotopic injection of PEc-overexpressing, normal prostate epithelium cells (HPrEC) in SCID mice was associated with increased metastatic rate. In humans, the IGF-1Ec expression was detected in prostate cancer biopsies, where its expression correlates with tumor stage. Our data describes the action of PEc in prostate cancer biology and defines its potential role in tumor growth, progression and metastasis.
The role of mechano growth factor in chondrocytes and cartilage defects: a concise review.
Mechano growth factor (MGF), an isoform of insulin-like growth factor 1 (IGF-1), is recognized as a typical mechanically sensitive growth factor and has been shown to play an indispensable role in the skeletal system. In the joint cavity, MGF is highly expressed in chondrocytes, especially in the damaged cartilage tissue caused by trauma or degenerative diseases such as osteoarthritis (OA). Cartilage is an extremely important component of joints because it functions as a shock absorber and load distributer at the weight-bearing interfaces in the joint cavity, but it can hardly be repaired once injured due to its lack of blood vessels, lymphatic vessels, and nerves. MGF has been proven to play an important role in chondrocyte behaviors, including cell proliferation, migration, differentiation, inflammatory reactions and apoptosis, in and around the injury site. Moreover, under the normalized mechanical microenvironment in the joint cavity, MGF can sense and respond to mechanical stimuli, regulate chondrocyte activity, and maintain the homeostasis of cartilage tissue. Recent reports continue to explain its effects on various cell types and sport-related tissues, but its role in cartilage development, homeostasis and disease occurrence is still controversial, and its internal biological mechanism is still elusive. In this review, we summarize recent discoveries on the role of MGF in chondrocytes and cartilage defects, including tissue repair at the macroscopic level and chondrocyte activities at the microcosmic level, and discuss the current state of research and potential gaps in knowledge.
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.
Loss of muscle mass and strength is a major problem during aging and the expression of Mechano Growth Factor (MGF), a member of the IGF-1 (insulin-like Growth Factor 1) super family, has been shown to be both exercise and age dependent. MGF, also called IGF-1Ec, has a unique E domain with a 49bp insert in humans (52bp in rodents; IGF-1Eb), which results in a reading frame shift during the IGF-1 gene splicing to produce a distinct mature isoform. We have studied the effects of the MGF-24aa-E peptide on proliferation and differentiation of primary human muscle cell cultures isolated from healthy subjects of different ages. We found that MGF-E peptide significantly increases the proliferative life span and delays senescence of satellite cells isolated from neonatal and young adult but not from old adult muscle, hypertrophy associated with a significant decrease in the percentage of reserve cells was observed in all cultures. It is concluded that the MGF-24aa-E peptide alone has a marked ability to enhance satellite cell activation, proliferation and fusion for muscle repair and maintenance and could provide a new strategy to combat age related sarcopenia without the oncogenic side effects observed for IGF1.
Increased expression of IGF-1Ec with increasing colonic polyp dysplasia and colorectal cancer.
IGF-1Ec is an isoform of Insulin-like growth factor 1 (IGF-1) and has recently been identified to be overexpressed in cancers including prostate and neuroendocrine tumours. The aim of this paper is to investigate the expression of IGF-1Ec in colorectal cancer and polyps compared to normal colon tissues and its association with recurrent disease using semi-quantitative immunohistochemistry. Immunohistochemistry for IGF-1Ec expression was performed for colorectal cancer, colorectal polyps and normal colonic tissues. The quantification of IGF-1Ec expression was performed with the use of Image J software and the IHC profiler plugin. Following ethics approval from the National Research Ethics Service (Reference 11/LO/1521), clinical information including recurrent disease on follow-up was collected for patients with colorectal cancer. Immunohistochemistry was performed in 16 patients with colorectal cancer and 11 patients with colonic polyps and compared to normal colon tissues and prostate adenocarcinoma (positive control) tissues. Significantly increased expression of IGF-1Ec was demonstrated in colorectal cancer (p < 0.001) and colorectal polyps (p < 0.05) compared to normal colonic tissues. Colonic adenomas with high-grade dysplasia had significantly higher expression of IGF-1Ec compared to low-grade dysplastic adenomas (p < 0.001). Colorectal cancers without lymph node metastases at the time of presentation had significantly higher IGF-1Ec expression compared to lymph node-positive disease (p < 0.05). No correlation with recurrent disease was identified with IGF-1Ec expression. IGF-1Ec is significantly overexpressed in colorectal cancer and polyps compared to normal colon tissues offering a potential target to improve colonoscopic identification of colorectal polyps and cancer and intraoperative identification of colorectal tumours.
Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer.
Insulin-like Growth Factor-1 (IGF-1) is a crucial mitogenic factor with important functions in the mammary gland, mainly through its interaction with the IGF-1 receptor (IGF-1R). This interaction activates a complex signaling network that promotes cell proliferation, epithelial to mesenchymal transition (EMT) and inhibits apoptosis. Despite extensive research, the precise molecular pathways and intracellular mechanisms activated by IGF-1, in cancer, remain poorly understood. Recent evidence highlights the essential roles of IGF-1 and its isoforms in breast cancer (BC) development, progression, and metastasis. The peptides that define the IGF-1 isoforms-IGF-1Ea, IGF-1Eb, and IGF-1Ec-act as key points of convergence for various signaling pathways that influence the growth, metastasis and survival of BC cells. The aim of this review is to provide a detailed exami-nation of the role of the mature IGF-1 and its isoforms in BC biology and their potential use as possible therapeutical targets.
Immunohistochemical expression of insulin-like growth factor-1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression.
Chronic hyperinsulinemia due to insulin resistance and elevated levels of insulin-like growth factor (IGF)-1 and IGF-2 are suggestive of a significantly higher risk of endometrial carcinoma. There is a wealth of evidence showing differential expression of IGF-1 isoforms in various types of cancer. In the present study, 99 archived endometrial carcinoma tissue sections were retrospectively assessed by immunohistochemistry for IGF-1Ec isoform expression. Expression of IGF-1Ec was also assessed in nine cases of non-neoplastic endometrial tissue adjacent to the tumor, in 30 cases with normal endometrium and in 30 cases with endometrial hyperplasia. Furthermore, the association between IGF-1Ec and the concurrent expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p53 or survivin was assessed, as well as their combined expression in association with clinicopathological variables. In endometrial carcinoma, IGF-1Ec expression was high in non-endometrioid carcinoma (serous papillary or clear cell carcinoma) compared with that in endometrioid adenocarcinoma. IGF-1Ec expression was also high in the presence of tumoral necrosis. Furthermore, there was a significant correlation between the histological differentiation and the sum of staining intensity and the number of IGF-1Ec immunopositive cells in endometrial carcinoma. There was a moderate negative correlation between co-expression of IGF-1Ec and PTEN, for both the number of immunopositive cells (P=0.006, ρ=-0.343) and the sum of staining (scores and intensity; P=0.006, ρ=-0.343). Furthermore, there was a positive correlation between the sum of staining (scores and intensity) and co-expression of IGF-1Ec and survivin (P=0.043, ρ=0.225). However, there was no association between concomitant expression of IGF-1Ec and p53. These results emphasized the importance of IGF-1Ec expression during development of non-estrogen dependent endometrial adenocarcinoma. IGF-1Ec and PTEN may function opposingly during endometrial carcinogenesis. By contrast, IGF-1Ec and survivin may share common molecular pathways and may promote, in parallel, tumoral development.
The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology.
Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target.
Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration.
The discovery that IGF-I mRNAs encoding isoforms of the pro-IGF-I molecule are differentially regulated in response to mechanical stress in skeletal muscle has been the impetus for a number of studies designed to demonstrate that alternative splicing of IGF-I pre-mRNA involving exons 4, 5, and 6 gives rise to a unique peptide derived from pro-IGF-I that plays a novel role in myoblast proliferation. Research suggests that after injury to skeletal muscle, the IGF-IEb mRNA splice variant is up-regulated initially, followed by up-regulation of the IGF-IEa splice variant at later time points. Up-regulation of IGF-IEb mRNA correlates with markers of satellite cell and myoblast proliferation, whereas up-regulation of IGF-IEa mRNA is correlated with differentiation to mature myofibers. Due to the apparent role of IGF-IEb up-regulation in muscle remodeling, IGF-IEb mRNA was also named mechano-growth factor (MGF). A synthetically manufactured peptide (also termed MGF) corresponding to the 24 most C-terminal residues of IGF-IEb has been shown to promote cellular proliferation and survival. However, no analogous peptide product of the Igf1 gene has been identified in or isolated from cultured cells, their conditioned medium, or in vivo animal tissues or biological fluids. This review will discuss the relationship of the Igf1 gene to MGF and will differentiate actions of synthetic MGF from any known product of Igf1. Additionally, the role of MGF in satellite cell activation, aging, neuroprotection, and signaling will be discussed. A survey of outstanding questions relating to MGF will also be provided.
Mechano growth factor E peptide regulates migration and differentiation of bone marrow mesenchymal stem cells.
IGF1Ec in humans or IGF1Eb in rodents (known as mechano growth factor (MGF)) has a unique E domain, and the C-terminal end of the E domain (MGF E peptide) plays important roles in proliferation, migration and differentiation of many cell types. Bone marrow mesenchymal stem cells (BMSCs) have multiple differentiation potentials and are considered as perfect seed cells for tissue repair. But the role of MGF E peptide on BMSCs is seldom investigated and the mechanism is still unclear. In this study, we investigated the effects of MGF E peptide on rat BMSCs (rBMSCs). Our results revealed that treatment with MGF E peptide had no effect on BMSC proliferation. However, both wound-healing and transwell assays indicated that MGF E peptide could significantly enhance rBMSCs migration ability. Further analysis indicated that MGF E peptide also reduced the expression levels of osteogenic genes, but increased the expression levels of adipogenic genes. Analysis of molecular mechanism showed that phosphorylation-Erk1/2 was activated by MGF E peptide and blockage of either Erk1/2 or IGF1 receptor could repress the migration effect of MGF E peptide. In conclusion, MGF E peptide is able to inhibit osteogenic differentiation but promote adipogenic differentiation. In addition, the migration effect of MGF E peptide on rBMSCs depends on IGF1 receptor via Erk1/2 signal pathway.
Possible role of the Ec peptide of IGF‑1Ec in cartilage repair.
The Ec peptide (PEc) of insulin-like growth factor 1 Ec (IGF-1Ec) induces human mesenchymal stem cell (hMSC) mobilization and activates extracellular signal‑regulated kinase 1/2 (ERK 1/2) in various cells. The aim of the present study was to examine the effects of PEc on the mobilization and differentiation of hMSCs, as well as the possibility of its implementation in combination with transforming growth factor β1 (TGF‑β1) for cartilage repair. The effects of the exogenous administration of PEc and TGF‑β1, alone and in combination, on hMSCs were assessed using a trypan blue assay, reverse transcription-quantitative polymerase chain reaction, western blot analysis, Alcian blue staining, wound healing assays and migration/invasion assays. It was determined that PEc is involved in the differentiation process of hMSCs towards hyaline cartilage. Treatment of hMSCs with either PEc, TGF‑β1 or both, demonstrated comparable cartilage matrix deposition. Furthermore, treatment with PEc in combination with TGF‑β1 was associated with a significant increase in hMSC mobilization when compared with treatment with TGF‑β1 or PEc alone (P<0.05). Thus, PEc appears to facilitate in vitro hMSC mobilization and differentiation towards chondrocytes, enhancing the role of TGF‑β1.
Effects of activity on growth factor expression.
For some time, it has been appreciated that muscle mass is regulated locally as well as systemically. We have cloned the cDNA of two isoforms of IGF-1, which are derived from the IGF-1 gene by alternate splicing. The expression of one of these was only detectable after mechanical stimulation. For this reason, this has been called mechano growth factor (MGF). The MGF is not glycosylated, is smaller, and has a shorter half-life in the unbound state than the systemic liver type IGF-1. As the result of a reading frame shift the MGF peptide also has a different C terminal sequence and thus has different binding protein/receptor affinities. Another splice variant (muscle L.IGF-I) is expressed in muscle during rest but is also upregulated by exercise. The latter is similar to the systemic liver type IGF-1. The evidence suggests that MGF has a high potency for inducing local protein synthesis and preventing apoptosis and therefore has an important role in local tissue repair and remodeling. Our physiological experiments show that stretch and particularly stretch combined with electrical stimulation, rather than stimulation alone are important in inducing MGF expression. The mechanotransduction mechanism is believed to involve the muscle cytoskeleton. During aging, the production of growth hormone and IGF-1 by the liver declines markedly. The discovery of MGF and muscle IGF-1 provides a link between physical activity and gene expression. This underlines the need for the elderly to remain active as the locally produced growth factors supplement the circulating IGF-1 levels.
Mechanochemical coupling of MGF mediates periodontal regeneration.
Clinical evidence shows that the mechanical stimulation obtained from occlusion could enhance periodontal ligament (PDL) remodeling. Mechano-growth factor (MGF) is a growth factor produced specifically following mechanical stimulus Here, we aim to investigate the mechanical enhancement potential and mechanism of the MGF in PDL regeneration. In vivo study found that MGF produced from the PDL under occlusion force could strongly enhance PDL remodeling. In vitro experiments and mathematical modeling further confirmed the mechanical enhancement effect of MGF for PDLSC differentiation toward fibroblasts. A mechanochemical coupling effect of MGF mediated the enhancement of mechanical effect, which was modulated by Fyn-FAK kinases signaling and subsequent MAPK pathway. Finally, enhanced PDL regeneration under the mechanochemical coupling of MGF and occlusal force was verified in vivo. There exists an additive mechanical effect of MGF mediated by Fyn-FAK crosstalk and subsequent ERK1/2 and p38 phosphorylation, which could be developed as an MGF-centered adjuvant treatment to optimize PDL remodeling, especially for patients with weakened bite force or destroyed periodontium.
Ageing and local growth factors in muscle.
Muscle responds to mechanical overload by increasing its size. In contrast, as a muscle gets older it atrophies. The mechanisms regulating these differing responses are not fully understood. Animal studies have shown that older muscles are less well able to repair following contraction-induced injury than young muscles. It is becoming clear that local growth factors produced within the muscle may play important roles in both repair, adaptation and ageing. The growth hormone/insulin like growth factor 1 (GH/IGF-I) axis is important during growth and development, but circulating levels of these hormones decline in later life. However, many tissues including muscle, produce IGF-I for autocrine and paracrine actions. Genetic manipulation of IGF-I in muscle has shown that it has considerable anabolic affects on muscle both in young and old animals. Insulin like growth factor 1 exists in multiple isoforms and one isoform, which differs from the systemic or liver type (IGF-IEa), appears to be particularly sensitive to mechanical signals and to muscle damage. This isoform (IGF-IEc) has been termed mechano growth factor (MGF). The anabolic actions of IGF-I and MGF are through stimulating protein synthesis and by playing a role in the activation, proliferation and differentiation of satellite cells. These effects are discussed in relation to human studies of muscle adaptation to strength training in older people who seem to retain an ability to increase muscle mass and strength through this type of exercise.
Mechano-growth factor regulates periodontal ligament stem cell proliferation and differentiation through Fyn-RhoA-YAP signaling.
Mechano-growth factor (MGF), which is a growth factor produced specifically in response to mechanical stimuli, with potential of tissue repair and regeneration. Our previous research has shown that MGF plays a crucial role in repair of damaged periodontal ligaments by promoting differentiation of periodontal ligament stem cells (PDLSCs). However, the molecular mechanism is not fully understood. This study aimed to investigated the regulatory effect of MGF on differentiation of PDLSCs and its molecular mechanism. Initially, we investigated how MGF impacts cell growth and differentiation, and the relationship with the activation of Fyn-p-YAPY357 and LATS1-p-YAPS127. Then, inhibitors were used to interfere Fyn phosphorylation to verify the role of Fyn-p-YAP Y357 signal after MGF stimulation; moreover, siRNA was used to downregulate YAP expression to clarify the function of YAP in PDLSCs proliferation and differentiation. Finally, after C3 was used to inhibit the RhoA expression, we explored the role of RhoA in the Fyn-p-YAP Y357 signaling pathway in PDLSCs proliferation and differentiation. Our study revealed that MGF plays a regulatory role in promoting PDLSCs proliferation and fibrogenic differentiation by inducing Fyn-YAPY357 phosphorylation but not LATS1-YAP S127 phosphorylation. Moreover, the results indicated that Fyn could not activate YAP directly but rather activated YAP through RhoA in response to MGF stimulation. The research findings indicated that the Fyn-RhoA-p-YAPY357 pathway is significant in facilitating the proliferation and fibrogenic differentiation of PDLSCs by MGF. Providing new ideas for the study of MGF in promoting periodontal regenerative repair.
Mechano-growth factor E-domain modulates cardiac contractile function through 14-3-3 protein interactomes.
In the heart, alternative splicing of the igf-I gene produces two isoforms: IGF-IEa and IGF-IEc, (Mechano-growth factor, MGF). The sequence divergence between their E-domain regions suggests differential isoform function. To define the biological actions of MGF's E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif. To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E18) and phospho-null (S/A18) peptides were delivered to mice at different doses for 2 weeks. Cardiovascular function was measured using echocardiography and a pressure-volume catheter. At the lowest (2.25 mg/kg/day) and highest (9 mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters. However, at 4.5 mg/kg/day the peptides produced opposing effects on cardiac function. Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry. Microarray analysis discovered 21 genes (FDR p < 0.01), that were expressed accordant with the opposing effects on contractile function at 4.5 mg/kg/day, with the nuclear receptor subfamily 4 group A member 2 (Nr4a2) identified as a potential target of peptide regulation. Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro. To determine the potential role of 14-3-3 proteins, we examined 14-3-3 isoform expression and distribution. 14-3-3γ localized to the myofilaments in neonatal cardiac myocytes, the cardiac myocytes and myofilament extracts from the adult heart. Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A18 peptide destabilized 14-3-3γ folding. Also, the S/A18 peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice. Conversely, the S/E18 peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3. Replacing the glutamic acid with a phosphate group on Ser 18 (pSer18), significantly increased 14-3-3γ protein stability. We conclude that the state of Ser 18 phosphorylation within the 14-3-3 binding motif of MGF's E-domain, modulates protein-protein interactions within the 14-3-3γ interactome, which includes proteins involved in the regulation of contractile function.
The role of the insulin-like growth factor 1 (IGF-1) in skeletal muscle physiology.
The human insulin-like growth factor-1 (IGF-1) gene gives rise to multiple, heterogeneous mRNA transcripts through a combination of multiple transcription initiation sites, alternative splicing and different polyadenylation signals. These IGF-1 mRNA transcripts code different isoforms of the precursor peptide of IGF-1 (IGF-1Ea, IGF-1Eb and IGF-1Ec or MGF in human skeletal muscle), which also undergo post-translational modification. There is increasing interest in differential expression and implication of IGF-1 isoforms in the regulation of muscle fiber regeneration and hypertrophy following mechanical overloading and damage. The identification of a locally expressed, loading- or damage-sensitive IGF-1 isoform in skeletal muscle was one of the most attractive developments in the context of the autocrine/paracrine actions of IGF-1. The concept that the competing processes of cellular proliferation and differentiation and the increased protein synthesis required for muscle repair or hypertrophic adaptation are regulated by a differential expression and by distinct roles of IGF-1 isoforms is discussed in the present review.
Mechano growth factor interacts with nucleolin to protect against cisplatin-induced neurotoxicity.
Mechano growth factor (MGF) is an alternatively spliced form of insulin-like growth factor-1 (IGF-1) that has shown to be neuroprotective against 6-hydroxydopamine toxicity and ischemic injury in the brain. MGF also induces neural stem cell proliferation in the hippocampus and preserves olfactory function in aging mice. Cisplatin is a chemotherapy drug that induces peripheral neuropathy in 30-40% of treated patients. Our studies were designed to see if MGF would protect dorsal root ganglion (DRG) neurons from cisplatin-induced neurotoxicity and to identify potential mechanisms that may be involved. Expression of endogenous MGF in adult DRG neurons in vivo ameliorated cisplatin-induced thermal hyperalgesia. Exogenous MGF and MGF with a cysteine added to the N-terminus (CMGF) also protected embryonic DRG neurons from cisplatin-induced cell death in vitro. Mass spectroscopy analysis of proteins bound to MGF showed that nucleolin is a key-binding partner. Antibodies against nucleolin prevented the neuroprotective effect of MGF and CMGF in culture. Both nucleolin and MGF are located in the nucleolus of DRG neurons. RNAseq of RNA associated with MGF indicated that MGF may be involved in RNA processing, protein targeting and transcription/translation. Nucleolin is an RNA binding protein that is readily shuttled between the nucleus, cytoplasm and plasma membrane. Nucleolin and MGF may work together to prevent cisplatin-induced neurotoxicity. Exploring the known mechanisms of nucleolin may help us better understand the mechanisms of cisplatin toxicity and how MGF protects DRG neurons.
IGF-IEc expression, regulation and biological function in different tissues.
Insulin-like growth factor I (IGF-I) is an important growth factor for embryonic development, postnatal growth, tissue repair and maintenance of homeostasis. IGF-I functions and regulations are complex and tissue-specific. IGF-I mediates growth hormone signaling to target tissues during growth, but many IGF-I variants have been discovered, resulting in complex models to describe IGF-I function and regulation. Mechano-growth factor (MGF) is an alternative splicing variant of IGF-I and serves as a local tissue repair factor that responds to changes in physiological conditions or environmental stimuli. MGF expression is significantly increased in muscle, bone and tendon following damage resulting from mechanical stimuli and in the brain and heart following ischemia. MGF has been shown to activate satellite cells in muscle resulting in hypertrophy or regeneration, and functions as a neuroprotectant in brain ischemia. Both expression and processing of this IGF-I variant are tissue specific, but the functional mechanism is poorly understood. MGF and its short derivative have been examined as a potential therapy for muscular dystrophy and cerebral hypoxia-ischemia using experimental animals. Although the unique mode of action of MGF has been identified, the details remain elusive. Here we review the expression and regulation of MGF and the function of this IGF-I isoform in tissue protection.
The role of mechano-growth factor E peptide in the regulation of osteosarcoma.
Osteosarcoma is one of the most common bone tumors, and exhibits a high degree of malignancy. Gene therapy is a novel approach to its treatment, however, specific target genes are required to enable effective use of this therapy. In order to investigate the effects of the mechano-growth factor E (MGF-E) peptide, which is derived from the IGF-I alternative splicing isoform, on the regulation of the development of osteosarcoma, the expression of MGF was detected in osteosarcoma cell lines with different degrees of malignancy. Concomitantly, exogenous MGF-E peptide was used to stimulate these osteosarcoma cell lines. The results demonstrated that MGF was overexpressed in malignant osteosarcoma cells, while it was not expressed in the least malignant osteosarcoma cells. Furthermore, MGF-E treatment altered the cell cycle distribution, and promoted the proliferation, migration and invasion of osteosarcoma cells. The possible mechanisms underlying these effects were detected by quantitative polymerase chain reaction and western blotting. Based on these results, it was hypothesized that MGF may be a suitable biomarker for malignant osteosarcoma phenotypes.
GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy.
Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.
Monoclonal antibodies to mechano-growth factor.
Two hybridoma clones secreting monoclonal antibodies (MAbs) to mechano-growth factor (MGF) have been produced by cell fusion technique. Isotyping of the MAbs revealed that both belong to the G1 subclass. The epitope specificity of the MAbs has been examined in competition experiments. No competition was detected, suggesting that the MAbs obtained recognize different antigenic determinants. MAbs of one clone (8B9) recognize human MGF peptide absent in insulin-like growth factor-1 (IGF-1) and comprising amino acids from 87 to 111. Affinity binding constants with the full-length MGF and 87-111 amino acid peptide have been determined by enzyme-linked immunosorbent assay (ELISA). A pair of monoclonal antibodies obtained can be used in a sandwich-type assay to quantify MGF.
Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.
Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.
Differential Expression of Insulin Growth Factor 1 (IGF-1) Isoforms in Different Types of Endometriosis: Preliminary Results of a Single-Center Study.
Endometriosis is a benign, estrogen-dependent gynecological condition with an uncertain exact pathogenetic mechanism. The aim of this study was to evaluate the potential differential expression of Insulin Growth Factor 1 (IGF-1) isoforms in deeply infiltrating endometriotic (DIE) lesions, in ovarian endometriomas, and in the eutopic endometrium of the same endometriosis patients and to compare their expression with that in the eutopic endometrium of women without endometriosis. A total of 39 patients were included: 28 with endometriosis, of whom 15 had endometriomas only, 7 had DIE nodules only, and 6 had both DIE and endometriomas, and 11 without endometriosis served as controls. We noticed a similar pattern of expression between IGF-1Ea and IGF-1Ec, which differed from that of the IGF-1Eb isoform, possibly implying differential biological actions of different isoforms in DIE subtypes. We observed a tendency of lower expression of IGF-1Ea and IGF-1Ec in endometriomas without DIE compared to endometriomas with concurrent DIE or in DIE nodules. In conclusion, differential expression of IGF-1 isoforms may indicate that DIE with its associated ovarian lesions and simple ovarian endometriosis should be considered as two forms of the disease developing under different molecular pathways.
Gene expression in muscle in response to exercise.
Muscle has an intrinsic ability to adapt to different types of work by changing fibre type and muscle mass. This process involves quantitative and qualitative changes in gene expression including those of the myosin heavy chain (MyHC) isogenes that encode different types of molecular motors. Increased expression of slow MyHC and of metabolic genes result in increased fatigue resistance. Recently, there has been some insight into how oxidative metabolism, as well as slow myosin expression, is regulated and the role of calcium in initiating switches in gene expression. In relation to muscle mass and power output it has been appreciated that local as well as systemic factors are important. Our group have cloned three types of IGF-I in human muscle which are derived from the IGF-I gene by alternative splicing. The expression of one of these that appears to be an autocrine/paracrine splice variant is only detectable after mechanical stimulation (MGF) and a systemic type (IGF-IEa) that is produced by the liver and other tissue including muscle. As the result of a reading frame shift, the MGF peptide has a different C terminal sequence to IGF-IEa. Interestingly, the MGF C terminal peptide has been found to act as a separate growth factor and to initially activate mononluceated myoblasts (satellite cells). MGF also responds to different signals and has different expression kinetics to IGF-IEa. The mechanotransduction mechanism for this signalling may directly or indirectly involve the dystrophin complex as dystrophic muscle, unlike normal muscle, is unable to express MGF in response to overload. Also the ability to express MGF has been found to decline markedly during ageing. The deficiency in expressing MGF and activating satellite cells in dystrophic and aged muscles may explain why muscle mass is not maintained in these situations. However, in normal muscle MGF appears to initiate local muscle repair with its over expression resulting in hypertrophy.
Fluorescence-Based Multiplex Western Blot to Simultaneously Detect the Insulin-Like Growth Factor-1 (IGF-1) Isoforms.
Insulin-like growth factor-1 (IGF-1) is critical for tissue growth and development. The IGF-1 gene contains six exons and due to alternative splicing three different isoforms might be produced: the IGF-1Ea, Eb, and Ec prohormones (proIGF-1s). These proIGF-1s share the same IGF-1 mature sequence, which is responsible for the IGF-1 receptor binding but differ in their carboxy-terminal extensions called Ea-, Eb-, and Ec-peptides. Several lines of evidence indicate that E-peptides control the intracellular proIGF-1s localization and maturation. Here, we present a multiplex Western blotting system able to simultaneously discriminate and quantify mature IGF-1, proIGF-1s and E-peptides within the same sample. HEK293 cells were transiently transfected with plasmids containing the IGF-1Ea, IGF-1Eb, or IGF-1Ec isoform or an empty vector. Two different primary antibodies, which recognize the mature sequence or the common region of E-peptides, were used to detect IGF-1 isoforms, which were subsequently distinguished with secondary antibodies conjugated to different fluorophores. Our results demonstrate the feasibility of simultaneously detecting different IGF-1 isoforms using two primary antibodies directed against different epitopes of proIGF-1s, combined with fluorescence-conjugated secondary antibodies. Furthermore, this dual-epitope strategy increases the specificity of protein detection, making it a valuable tool for studying the diverse roles of IGF-1 isoforms in biological processes.
Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells.
A splice form of IGF-1, IGF-1Eb, is upregulated after exercise or injury. Physiological responses have been ascribed to the 24-amino acid COOH-terminal peptide that is cleaved from the NH3-terminal 70-amino acid mature IGF-1 protein. This COOH-terminal peptide was termed "mechano-growth factor" (MGF). Activities claimed for the MGF peptide included enhancing muscle satellite cell proliferation and delaying myoblast fusion. As such, MGF could represent a promising strategy to improve muscle regeneration. Thus, at our two pharmaceutical companies, we attempted to reproduce the claimed effect of MGF peptides on human and mouse muscle myoblast proliferation and differentiation in vitro. Concentrations of peptide up to 500 ng/ml failed to increase the proliferation of C2C12 cells or primary human skeletal muscle myoblasts. In contrast, all cell types exhibited a proliferative response to mature IGF-1 or full-length IGF-1Eb. MGF also failed to inhibit the differentiation of myoblasts into myotubes. To address whether the response to MGF was lost in these tissue culture lines, we measured proliferation and differentiation of primary mouse skeletal muscle stem cells exposed to MGF. This, too, failed to demonstrate a significant effect. Finally, we tested whether MGF could alter a separate documented in vitro effect of the peptide, activation of p-ERK, but not p-Akt, in cardiac myocytes. Although a robust response to IGF-1 was observed, there were no demonstrated activating responses from the native or a stabilized MGF peptide. These results call in to question whether there is a physiological role for MGF.
Mechano-growth factor E peptide promotes healing of rat injured tendon.
To determine the possible beneficial effects of a synthetic mechano-growth factor E peptide (MGF-C25E) on the healing of rat Achilles tendon. A significantly increased Achilles functional index was found in the MGF-C25E-treated tendons relative to the saline-treated tendons. Macroscopic observation showed that the repair of MGF-C25E-treated (1000 ng/ml) tendons was superior to that of the saline-treated tendons. The mean value of the stiffness of the repaired tendons was significantly increased in the MGF-C25E-treated (1000 ng/ml) tendons relative to the saline-treated tendons. Moreover, histological analysis provided evidence of tissue remodeling and cell alignment. MGF-C25E plays an important role in promoting healing of injured rat tendon and could be used as a potential therapeutic factor for tendon repair.
Mechano-growth factor, an IGF-I splice variant, rescues motoneurons and improves muscle function in SOD1(G93A) mice.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration. Although viral delivery of IGF-I has shown therapeutic efficacy in the SOD1(G93A) mouse model of ALS, clinical trials of IGF-I in ALS patients have led to conflicting results. Here we examine the effects of an IGF-I splice variant, mechano-growth factor (MGF) which has previously been shown to have greater neuroprotective effects than IGF-I in a number of models of neurodegeneration. A mammalian expression plasmid containing either MGF or, for comparison, the IGF-I cDNA sequence was delivered to the hindlimb muscles of SOD1(G93A) mice at 70 days of age, at symptom onset. Treatment with either IGF-I or MGF resulted in a significant improvement in hindlimb muscle strength, and an increase in motor unit and motoneuron survival. Significantly more motoneurons survived in MGF treated mice.
Mechano growth factor E peptide promotes osteoblasts proliferation and bone-defect healing in rabbits.
To assess the potential efficacy of mechano growth factor (MGF) for bone injury, we firstly investigated the effects of growth factors, including MGF, its E peptide (a short 24-amino acid C-terminal peptide, MGF-Ct24E), and insulin-like growth factor 1(IGF-1) on MC3T3-E1 osteoblast-like cell proliferation. MGF-Ct24E had the highest pro-proliferation activity among three growth factors, which was 1.4 times greater than that of IGF-1. Moreover, MGF-Ct24E promoted cell proliferation by inducing cell cycle arrest in the S and G(2)/M phase of the cell cycle, but also mainly by the activation of the MAPK-Erk1/2 pathway. In vivo, a 5-mm segmental bone defect in the radius of 27 rabbits was treated with MGF-Ct24E by two doses (28.5 and 57 μg /kg body weight) vs. non-growth factor injection for five consecutive days postoperatively. The cumulative rate of radiographically healed defects and histological scores of bone defect-healing revealed a statistical difference between high-dose treatment and non treatment (p < 0.01), which showed the treatment promoted defect healing. This report is the first to demonstrate that MGF-Ct24E possesses positive effects on osteoblast proliferation and bone-defect healing, suggesting a new strategy in fracture healing.
Mechano-growth factor E peptide inhibits the differentiation and mineralization of osteoblasts.
To investigate the effects of mechano-growth factor E (MGF-E) peptide derived from an IGF-1 isoform on the differentiation and mineralization of osteoblasts. MGF-E peptide corresponding to the carboxy terminal 24 amino acid peptide of human MGF was synthesized. MGF-E (1 nM) peptide was then used to treat the pre-osteoblast line MC3T3-E1. At predetermined times, alkaline phosphatase (ALP) activity was quantified using an enzyme activity assay kit. The expression levels of collagen I (Col I) and osteopontin (OPN), and core binding factor 1 (Cbfα-1) were detected by reverse transcription polymerase chain reaction and Western blot analysis. The effect of MGF-E on mineralization was determined by Alizarin Red staining and calcium concentration analysis. The kinase inhibitor PD98059 was used to investigate Erk pathway involvement in the MGF-E role. In the MGF-E-treated osteoblasts, ALP activity decreased with increased Erk activation. The transcription and translation of Col I were inhibited, but those of OPN were enhanced. PD98059 abolished the inhibitory effect and increased the expression of Col I, but decreased that of OPN. Treatment with MGF-E alone up-regulated the mRNA and total protein levels of Cbfα-1, but decreased the fraction of activated Cbfα-1 in the nucleus. Mineralization was delayed by MGF-E, as shown by the bone nodule staining and calcium concentration analysis. These delayed actions were weakened after treatment with PD98059. MGF-E could inhibit osteoblast differentiation and mineralization. The possible mechanisms are increased Erk activity and decreased Cbfα-1 nuclear translocation.
The Roles of IGF-1 and MGF on Nerve Regeneration under Hypoxia- Ischemia, Inflammation, Oxidative Stress, and Physical Trauma.
Nerve injuries and lesions often lead to the loss of neural control, reducing the patients' quality of lives. Nerve self-repair is difficult due to the low regeneration capacity, insufficient secretion of neurotrophic factors, secondary complications, and adverse microenvironmental conditions such as severe hypoxia-ischemia, inflammation, and oxidative stress. Effective therapies that can accelerate nerve regeneration have been explored. Cytokine therapy can significantly improve neural survival and myelin regeneration during nerve repair. Insulin-like growth factor-1 (IGF-1) and its isoforms (IGF- 1Ea and IGF-1Eb/Ec [also known as MGF]) represent a promising therapeutic approach regarding nerve repair, given their well-described proliferative and anti-apoptotic capacities on neurons withstanding the adverse environmental conditions. This review summarizes the research progress regarding the effects of IGF-1 and its isoforms on nerve repair after nerve injury, hypoxic-ischemic insult, inflammation, and oxidative stress. We provide a theoretical basis for the clinical treatment of nerve injuries.
IGF-1 expression in infarcted myocardium and MGF E peptide actions in rat cardiomyocytes in vitro.
Insulinlike growth factor-1 (IGF-1) expression is implicated in myocardial pathophysiology, and two IGF-1 mRNA splice variants have been detected in rodents, IGF-1Ea and mechano-growth factor (MGF). We investigated the expression pattern of IGF-1 gene transcripts in rat myocardium from 1 h up to 8 wks after myocardial infarction induced by left anterior descending coronary artery ligation. In addition, we characterized IGF-1 and MGF E peptide action and their respective signaling in H9C2 myocardial-like cells in vitro. IGF-1Ea and MGF expression were significantly increased, both at transcriptional and translational levels, during the late postinfarction period (4 and 8 wks) in infarcted rat myocardium. Measurements of serum IGF-1 levels in infarcted rats were initially decreased (24 h up to 1 wk) but remained unaltered throughout the late experimental phase (4 to 8 wks) compared with sham-operated rats. Furthermore, specific anti-IGF-1R neutralizing antibody failed to block the synthetic MGF E peptide action, whereas it completely blocked IGF-1 action on the proliferation of H9C2 cells. Moreover, this synthetic MGF E peptide did not activate Akt phosphorylation, whereas it activated ERK1/2 in H9C2 rat myocardial cells. These data support the role of IGF-1 expression in the myocardial repair process and suggest that synthetic MGF E peptide actions may be mediated via an IGF-1R independent pathway in rat myocardial cells, as suggested by our in vitro experiments.
Quick links (PubMed)
- PMID 24776619 — 2014 · Biological activity of the e domain of the IGF-1Ec as addressed by synth…
- PMID 12023866 — 2002 · Gene expression in skeletal muscle.
- PMID 20564425 — 2010 · Preferential expression of IGF-1Ec (MGF) transcript in cancerous tissues…
- PMID 20844834 — 2011 · Insulinlike growth factor-1Ec (MGF) expression in eutopic and ectopic en…
- PMID 33732968 — 2021 · Surface modification of electrospun fibers with mechano-growth factor fo…
- PMID 15501012 — 2004 · Growth factors and muscle ageing.
- PMID 30134795 — 2018 · IL-6 is associated to IGF-1Ec upregulation and Ec peptide secretion, fro…
- PMID 34015701 — 2021 · Pretreatment with mechano growth factor E peptide attenuates osteoarthri…
- PMID 25569803 — 2015 · Oncogenic Role of the Ec Peptide of the IGF-1Ec Isoform in Prostate Canc…
- PMID 37171185 — 2023 · The role of mechano growth factor in chondrocytes and cartilage defects:…
- PMID 21354439 — 2011 · Mechano Growth Factor E peptide (MGF-E), derived from an isoform of IGF-…
- PMID 32772171 — 2020 · Increased expression of IGF-1Ec with increasing colonic polyp dysplasia …
- PMID 39273251 — 2024 · Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Br…
- PMID 33193855 — 2020 · Immunohistochemical expression of insulin-like growth factor-1Ec in prim…
- PMID 27931832 — 2016 · The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophy…
- PMID 20130113 — 2010 · Minireview: Mechano-growth factor: a putative product of IGF-I gene expr…
- PMID 24323763 — 2014 · Mechano growth factor E peptide regulates migration and differentiation …
- PMID 27571686 — 2016 · Possible role of the Ec peptide of IGF‑1Ec in cartilage repair.
- PMID 11915923 — 2001 · Effects of activity on growth factor expression.
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