Historical text by DatBTrue, written between 2008 and 2016 and reproduced verbatim. It records what was argued then; it is not dosing guidance and not medical advice. Read the disclaimer.
To quickly summarize the difference in function, MGF stimulates muscle stem cells (satellite cells) to reenter the cell cycle and proliferate, whereas IGF-1 is necessary for the differentiation of newly generated muscle precursor cells into myoblasts and myofibers.See material from Goldspink posted earlier in this thread at: Post #158 Mechanical Signals, IGF-I Gene Splicing, and Muscle Adaptation
Growth Hormone bound to its receptor in the liver activates the STAT5b signaling pathway which promotes movement of that activated signaling protein to the nucleus where it induces transcription of the IGF-1 gene. From studies in mice and humans, it is evident that GH induces expression of both the endocrine form of IGF-1, the muscle form of IGF-1 and MGF. 1 Mice deficient in GH (lit/lit mice) respond to administration of GH with an acute increase in MGF, but not IGF-1, in skeletal muscle, although IGF-1 in liver is increased. 2 However the precise mechanism by which GH has distinct effects on IGF-1 and MGF expression in muscle is not completely known.
What is known is that in response to stretch overload and the presence of growth hormone combined gene transcription in muscle and its subsequent “blueprint” assembly” are induced to create mechano growth factor (MGF also known as IGF-1Ec in humans or IGF-1EB in mice) instead of muscle IGF-1.
How does the behavior of IGF-1 and MGF differ?
“MGF is a non-secreted form of IGF-1 that can be found in the nucleus of cells in culture or in a perinuclear location in hippocampal cells after ischemia (restriction in blood supply)”.
In other words MGF never leaves the cell it was created in. For emphasis I quote from another source:
“…MGF… is not normally secreted.”
Geoffrey Goldspink has written “that MGF increases myoblast proliferation via a different signalling pathway” then IGF-1.
To reiterate & expand upon this concept I quote from another source:
“IGF-1 isoforms differ in the signaling pathways they activate. By over-expressing IGF-1Ea and MGF in muscle, it has been shown that both isoforms can activate IGF-1R and AKT phosphorylation. In addition, MGF was shown to induce phosphorylation of ERK, a property not shared with IGF-1Ea.”
So IGF-1 and MGF work through different pathways not receptors. There is only one receptor, IGF-1-receptor (also insulin, IGF-II & hybrid receptors which are not relevant to this discussion). There is no MGF receptor. The reason why it would be nonsensical to have an MGF receptor is that MGF does not leave the cell.
This contrasts with IGF-1 which is released from the liver into circulation and which is created in muscle and translocates to the cell surface. Both events result in IGF-1 binding to the IGF-1 receptor.
So what happens in plain language please?
During the process of gene transcription pieces of DNA are transcribed and then spliced together by RNA and this code is taken to the ribosomes where the peptide is manufactured. In splicing MGF there is a subtle frame shift such that the right side of the code is a little different then IGF-1. Everything else is identical.
This subtle difference means that when MGF & IGF-1 are manufactured by the riboomes MGF MUST because of the signal pull that is part of its make up, translocate to the Nucleus of the cell and more specifically the Nucleolus.
IGF-1 because of its makeup MUST move to the cytoplasm where it forms a pool of IGF-1 which will transloacte to the cell membrane where it will bind w/ an IGF-1 receptor.
MGF has NO receptor. It does not need it to mediate events. Too many times people think that a lock/key ligand/receptor is needed to intiate signals. That is not always true especially when proteins move to the nucleus.
MGF is NEVER found in circulation. It is produced in a muscle cell as described and it will act there always.
IGF-1 however does circulate. It is produced in the liver and secreted into the blood stream. If it is made in muscle tissue or in local tissue it makes its way to the surface and can bind to a receptor on that cell or nearby cells. The latter is how muscle made IGF-1 can effect nearby bone growth.
In lab experiments with MGF they usually do one of two things. One they use a viral vector of MGF cDNA to increase the cDNA of MGF in the cell so that more MGF is made internally. When they do this they get a 25% increase in muscle in a three week period. If they use the same approach to get IGF-1 to express itself from within they get less muscle growth (15%) and it takes 4 months.
The second approach is to actually inject MGF into a cell (i.e. penetrate the cell membrane). Unfortunately for scientists this also invokes a damage repair function in cells so it is difficult to actually attribute all of the benefits that ensue to MGF.
You follow neither of these approaches when you inject MGF or Peg MGF.
MGF is identical to IGF-1 in chemical makeup on the leftside of the peptide. This allows it to bind with IGF-1 receptors should it ever be injected or find itself outside of the cell. However because of the difference in right-side structure MGF is incapable of binding to IGF-1 binding proteins (which would prolong its life).
MGF has a very short half-life in blood plasma. If it is pegylated it has a longer half-life. I do not know the extent to which pegylation reduces binding affinity but it probably does to some extent depending on where it is pegylated.
Injecting Peg MGF will, if it survives, probably bind to an IGF-1 receptor. If it does so it activates the IGF-1 signaling pathways just as IGF-1 would.
I do not have any data on how strongly MGF will bind to IGF-1 receptors. A pegylated MGF is small enough to penetrate the vascular wall and travel systemically. It will not be confined to the area injected as IGF-1 bound to IGF-BindingProtein3 bound to Acid laibile subunit (i.e. the ternary complex) will. Thats why injecting large amounts of MGF brings vacularization, pumps, glucose uptake, in essence insulin-like activity….because it is behaving as IGF-1…and doing so in systemic fashion.
Some science (derived from ref:5) followed by both a reiteration and an elaboration on my part.
The IGF-1 gene consists of 6 exons (DNA bases that are transcribed into mRNA and eventually code for amino acids in the proteins), separated by 5 introns (DNA bases, which are found between exons, but are not transcribed). Transcription is controlled by alternate use of two upstream promoters and starts at several transcription start sites located in exons 1 and 2. Together, alternate promoter usage and alternative splicing at the 5′ and 3′ ends of the gene generate several distinct mRNAs depending on their exon sequences, which code for three isoforms of precursor IGF-1.
Note: The notation 5′ and 3′ refer to the direction of the DNA template in the chromosome and is used to distinguish between the two untranslated regions (grey).
These isoforms have characteristic N-terminal signal peptide sequences and C-terminal extension (E) peptide domains. Exons 1 and 2 and part of exon 3 encode the signal peptides. The remainder of exon 3 and exon 4 encode the mature IGF-1 peptide and the proximal part of the E peptide, which are shared by all isoforms. Splicing of exon 4 to exon 6 generates the predominant transcript IGF-1Ea. Splicing of exon 4 to exon 5 generates IGF- 1Eb, which encodes an isoform with 47 distinct amino acids in the E domain. When part of exon 5 is spliced to exon 6, the IGF- 1Ec (IGF-1EB in mouse) variant is generated. In this case, a frame-shift occurs in exon 5 followed by premature transcription stop in exon 6 that results in a stretch of 25 amino acids unique to this variant.
As a result these templates produce in cellular ribosomes IGF-1 peptide forms that differ in amino acid structure in the E peptide region. This results in different C-terminal regions for the IGF-1 & MGF peptides. MGF BECAUSE of its C-terminal sequence, upon “birth” becomes rapidly localized in the nucleus. It is the carboxy portion which draws either MGF or the altered portion to the nucleus rather than to the cell membrane.
“We found that the isoform of the human IGF-I precursor encoded by exon 5 [MGF] localized to the nucleus and strongly to the nucleolus. Precursors containing exon 6 or the upstream portion of exon 5 did not…The findings are consistent with the presence of a nuclear and nucleolar localization signal situated in the C-terminal part of the exon 5-encoded domain.”
MGF is an autocrine growth factor, and this is THE different signaling pathway…a pathway that does not involve any receptor. The action of MGF via this pathway is one of promoting myoblast proliferation.
However MGF maintains a dual action. It “activates the muscle stem cell pool through its C-terminal domain (encoded in exons 5 and 6) as mentioned above AND according to the various studies by Geoffrey Goldspink “increases anabolic effects as the result of its IGF-I receptor binding domain (encoded in exons 3 and 4), which all the IGF-I genes possess.”
The unaltered portion of MGF is still capable of binding to the IGF-Receptor. The altered carboxy portion renders MGF incapable of binding to the IGF-1-Binding proteins BUT it possesses the ability to bind to the IGF-1-Receptor via the unaltered side.
So what if MGF is injected into plasma? Presumably it would bind to the IGF-1-Receptor and initiate the AKT signaling pathway which will stimulate cell growth signals. In other words MGF stops being MGF and behaves like IGF-1 in initiating anabolic events. But it has been shown but is not yet fully understood that MGF is capable of AKT phosphorylation (an IGF-1-IGF-1-receptor mediated event) without ever coming in contact with the IGF-1-receptor.
This brings up an interesting point. MGF seems to be capable of performing both its unique duties and those of IGF-1 as well (at times).
What about studies that inject MGF into subjects?
Actually they don’t do it that way.
“One of the methods we used to establish the biological action of MGF was to engineer a gene into which its cDNA was inserted into a vector. To our surprise a single intramuscular injection into a mouse muscle resulted in a 25% increase in mean muscle fibre cross section area within three weeks.” – Goldspink G, Yang SY. Method of treating muscular disorders, United States Patent. Patent No US 6,221,842 B1, Apr 24, 2001.
This contrasts with, “similar experiments carried out using the systemic or liver type of IGF-I in an adenoviral vector under the control of a muscle regulatory sequence. This took four months to produce a 15% increase and is probably due to the anabolic effect of IGF-I, which is common to all the splice variants.” – Barton-Davis E, Shoturma DI, Musaro A, et al. Viral mediated expression of insulin-like growth factor-I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci USA 1998;95:15603