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MGF - продвинутое понимание

Тема в разделе "Пептиды", создана пользователем zphc_pep, 14 сен 2016.


 
    1. zphc_pep

      zphc_pep Амбал

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      The IGF-1 gene contains 6 exons. An exon is a nucleotide sequence encoded by a gene that means something. It is so meaningful that it is copied and becomes part of final mature RNA product. There are sequences of nucleotides between the meaningful parts (exons) that are rubbish. They are named introns and discarded.

      The term exon basically means a chunk of meaningful sequence in the DNA. It also refers to that same chunk as it has been copied into an RNA transcript. So an exon in a gene will once it is copied into RNA also be called an exon. We can refer to these chunks by naming the gene and than assigning that chunk or exon a number. An example would be IGF-1 gene, exon 1. The next meaningful chunk would be called exon 2 and so on.

      The final RNA transcripts are created through a process called RNA splicing. This process removes the rubbish introns and then joins the meaningful exons into what will become the mature messenger RNA which will carry the code to ribosomes where a protein based on that code will be created.

      The IGF-1 gene contains several exons and because they are spliced and arranged in a couple of different ways, gives rise to several mRNA (messenger RNA) transcripts by alternative splicing. The different IGF-1 mRNA transcripts encode several precursor proteins, which differ by the length of the amino-terminal called the signal. Think of the signal potion as the transmitter responsible for guiding the peptide to where it needs to go in order to be secreted out of the cell. In addition the precursor proteins also differ by the structure of the other side, the carboxy-terminal end of the sequence, called the extension peptide (E-Peptide).

      After the ribosomes have produced several IGF-1 varieties of precursor polypeptides (isoforms) they are all cleaved or chopped (undergo posttranslational (i.e. making of the protein) cleavage) to produce both the mature IGF-1 peptide (which was encoded by exons 3 and 4) which binds with IGF-1 receptors and several different E-domain peptides (which contain different parts of exon 5 and or 6) and which freelance... they act autonomously.

      As you can see in the figure below the mature peptide IGF-1 results when the three E-domain peptides are cleaved off. The signal peptide remains with it until it has mad it's way into the secretion channels where it is cleaved off.

      The IGF-1 EC peptide (one of those remaining freelancing E-domain peptides left on the other side) that remains from the cleaving process is also called MGF (Mechano Growth Factor). I prefer to refer to it as native MGF as it differs from exogenous synthetic MGF. This EC peptide is an exon 4-5-6 variant. From the figure below you can see that synthetic exogenous MGF E-peptide is made up of 24 of the amino acids of native MGF. These 24 amino acids include the last 24 of the carboxy-terminal side of native MGF.

      It is often stated that these autonomous E-peptides remain within the cells of their birth where they act while the mature IGF-1 leaves the birthing cell and eventually mediates its actions through binding to specific receptors, such as the type 1 IGF receptor (IGF-1R), the insulin receptor (IR), and the hybrid IR/IGF-1R. The IGF-1R and IR are cell surface heterotetrameric tyrosine kinase receptors that are coupled to intracellular signaling pathways, such as the ras-raf-MAPK-ERKs and PI3K-AKT signaling cascades. That's just how they roll.
      [​IMG]
      For the longest time a series of questions remained. Will native MGF outside the cell of it's birth have any affect? If so is it through the same cell surface receptors IGF-1 acts through? Is there a distinct MGF receptor? Finally a question germane to us... Does the synthetic exogenous MGF peptide have any affect from outside the cell and does it act through a distinct receptor?

      I believe we can answer the latter question to our satisfaction now. In specific regard to synthetic exogenous MGF, provided that it contains the amino acid swaps to make it resistant to quick degradation it should have proliferative activity in vivo. It has been shown to be very potent in vitro and to act via a distinct receptor/molecule.

      In a recent study by Milingos DS, they silenced the IGF-1R and IR (insulin receptor) and witnessed proliferative activity by exogenous MGF E-peptide. In their words this suggests

      "that synthetic MGF E-peptide action is apparently mediated via an IGF-1R–independent, IR- independent mechanism. Because the IR/IGF-1R hybrid receptor consists of IR and IGF-1R hemi-receptors, the silencing of the IR or the IGF-1R is expected to block the formation of the hybrid receptor. Therefore, our experiments suggested that mitogenic activity of the synthetic MGF E-peptide is mediated via another receptor molecule.

      Further evidence for such autonomous actions of the synthetic MGF E-peptide was provided by our recent data, which revealed that MGF E-peptide activated ERK1/2 phosphorylation but did not activate AKT phosphorylation in skeletal muscle–like and myocardial-like cells. This particular phosphorylation pattern generated by the MGF E-peptide...[suggests] that MGF E-peptide activity is via an IGFR/IR-independent mechanism and via an as yet unidentified molecule." - Insulinlike growth factor-1Ec (MGF) expression in eutopic and ectopic endometrium: characterization of the MGF E-peptide actions in vitro, Milingos DS, Mol Med. 2011 Jan-Feb;17(1-2):21-8

      Interesting Clue

      So why go through all of the gene to mRNA, exons and cleavage discussion? Well I had a big article I wrote last year which seems to have been uploaded by me right when we moved our forum to a new server and we lost several hours worth of data and I believe that my article was one of the things lost. I didn't realize it until recently... in that article among other things I emphasize that the vast majority of studies do not distinguish between the several mRNA (messenger RNA) IGF-1 transcripts which are created by alternative splicing when they write of mRNA for IGF-1. Strangely these studies go on to assume that the measure mRNA for IGF-1 would result in the IGF-1 form that circulates and binds to cellular membrane IGF-1 receptors. This is important because forums (other than this one) often compound the mistake by attempting to translate these studies into something useful.
      Okay, that's not really why we went through the exercise but it is something I wanted to point to. No the reason we are in this paragraph is that there are some interesting clues left to us in the study Gene Expression in Response to Muscle Stretch, Geoffrey Goldspink, Clinical Orthopaedics And Related Research Number 403S, pp. S146–S152 2002 They mention a binding protein in muscle for MGF that is different from any IGF-1 binding proteins. "Therefore, this splice variant of IGF-I [MGF] has a domain that results in it binding to a different binding protein and a different mode of action to the systemic IGF-I's. Using a proteomics approach, the current authors identified the muscle-specific protein that binds MGF. This would be expected to localize its action because it would be unstable in the unbound form."
      They than write, "This is important as its production would not disturb unduly the glucose homeostasis mechanism." The implication is that unbound WOULD disturb glucose homeostasis. For the reason that we are administering unbound "naked" MGF in the form of synthetic exogenous MGF this is a ponderable statement ESPECIALLY in light of the increase in muscle energy and in apparent glycogen storage that comes with large dosings of MGF. We know that native IGF-1 can stimulate glucose transport in fat and muscle, inhibit hepatic glucose output and lower blood glucose while simultaneously suppressing insulin secretion but it acts through receptors. - Role of insulin-like growth factor in maintaining normal glucose homeostasis, Clemmons DR, Horm Res. 2004;62 Suppl 1:77-82 MGF anecdotally and if the study clue in regard to MGF binding protein is to be accepted at face value appears to do this as well, but not through the insulin or IGF-1 receptors.

      If you reexamine the figure above you will see that synthetic exogenous MGF share the final 24 amino acids with native MGF which includes the C-terminal (carboxy terminal). So it should by my reading of the following, be just as capable of binding to MGF binding proteins as the native form.

      "The fact that MGF has a muscle-specific binding protein is thought to be attributable to the reading frame shift, which produces a different C terminal and therefore a different binding protein recognition sequence. Although the mRNA for MGF was detectable after mechanical stimulation; the MGF peptide in the bound state also was detectable only at a lower level in resting and non-injected muscles. It is probable that this is residual MGF from an earlier bout of activity and shows the delayed release function of the MGF binding protein. This explains why intermittent bouts of exercise, every other day, are sufficient to produce muscle hypertrophy." - Geoffrey Goldspink (2002)

      I often prefer to leave things open and just walk away from the statements, but I know people like conclusions. Mine would be that exogenous synthetic MGF likely has a receptor or cell surface molecule through which it may act; it can have an impact on glucose homeostasis in a way that increases both the ability to do work in the gym and recover; that it can bind with an MGF binding protein (however such a binding protein would need to be in muscle outside the cell). From my study of the ternary complex with IGF-1 (which is IGF-1 bound to a binding protein bound to acid-labile subunit) I know that IGF-1 is loosely bound and sort of hovers near cells whereupon should the cell express receptors the IGF-1 would have a stronger attraction to the receptor than the binding protein (or ternary complex) and go to the receptor and bind. Similar thoughts could apply to muscle. Perhaps this mysterious MGF receptor makes an appearance or is expressed only upon muscle trauma. We do know that stretch overload does release IGF-1 into circulation... which means the liver is not the only source of circulating IGF-1. Does native MGF release as well and enter neighboring muscle tissue? Can exogenous synthetic MGF meet released binding proteins post trauma thereby extending both life and potential availability to tissue? ...in a time-released manner? There are a lot of specific unknowns... but we have a better picture now than we had before.
      I want to also reiterate that current studies of all ilk provide information on IGF-1 isoforms mainly at the mRNA level, since the available techniques do not permit both the identification and the "differential quantitation of the different
      IGF-1 isoforms at the protein level." So in other words they can not be relied on for our purposes although they are often used by arm-chair muppets to vociferously argue the importance of this now almost meaningless term "IGF-1".

      Finally in the Toggling forum I will write of optimum resistance exercise bout frequency so as to initiate and invigorate as well as sustain increases in both MGF transcripts as well as intracellular pathways that increase muscle protein synthesis. Understand that this posting does not make mention of what it is we expect MGF to do for us. That is located elsewhere. Suffice to say hypertrophy comes from an increase in net muscle protein synthesis AND a balance of proliferation and subsequent differentiation of the donated muscle cell nuclei capable of increasing what appears to be the limiting factor in muscle size growth... the bottle neck is the initiation of transcription.
       
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    2. Жиробашка

      Жиробашка Бог мемов

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      надоело через гугл транслейтор переводить - ебитесь сами!:D
       
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    3. Жиробашка

      Жиробашка Бог мемов

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      жаль что у ТС нету своего мнения и он цитирует хуй знает кого:D
       
    4. Daniskinson

      Daniskinson mr.Champion

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      Да хуй бы с ним, переводит в два счета, но вот как читать эту хуйню полученную?)))
       
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    5. ZPHC Russia

      ZPHC Russia Дилер

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      ZPHC
      это очень авторитетный автор, сложно читать переведенные статьи гуглом, в оригинале читается намного легче, поэтому.
      А перевести на русский достойно - очень долго и сложно все таки.
       
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    6. Daniskinson

      Daniskinson mr.Champion

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      Вот в том то и дело, что долго и сложно(
       
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    7. fantom84

      fantom84 mr.Champion

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      В итоге получается бесполезный топик. Никто не будет сидеть и читать на английском, думаю. И трёх человек, настолько сильно интересующихся пептидами и владеющих мед.терминологией не наберется...
       
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    8. Жиробашка

      Жиробашка Бог мемов

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      во первых не указано кто автор - то что он "авторитетный" я не знаю по каким критериям угадать.
      конечно тяжело читать переведенные гуглом статьи, которыми zphc_pep засрал пол форума
      ну если не хотите вносить никакой вклад в развитие форума и ленитесь нормально перевести статью - то это не наша проблема. я уже прелагал заказать перевод на адвего на крайняк, но видимо нет на это денег...
      лучше вообще молча сидеть чем выкладывать текст на английском без указания автора - на форуме где подобные тексты даже на русском будет читать и вдумываться в прочитанное 1-2% пользователей
       
      Последнее редактирование: 15 сен 2016
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    9. Жиробашка

      Жиробашка Бог мемов

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      так кто этим должен заниматься? разве пользователи? вон Gustavo Fring пишет САМ статьи, тратит ли он своё время на качественный перевод или использует свой мозг чтобы все нам разжевать не знаю но читать хотябы можно на русском и то там хуй проссышь о чем речь - ведь мы не физики-ядерщики тут собрались а простые кочки...

      мой первый пост был адресован ТСу кстати а не был попыткой перевести ЭТО :D
       
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    10. zphc_pep

      zphc_pep Амбал

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      Мы уже имеем опыт с переводчиком англ инф от Митсу(mitsu) украинец Дима Устименко, и его горе -переводами, оформленные красиво внешне и даже напечатанные в в железном мире, но сильно урезанные, либо с ошибками, потому в оригинале.

      ок, но пожелания мы поняли, приступим как только будет время.
       
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