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GF-1, GHRP, Testosterone, Trenbolone & Nandrolone Primer [entire thread...] (What you should read if you don't want to be a beginner)
I think it's important to start off by visualizing an interesting distinction between peptide hormones such as insulin and growth hormone and the peptide hormone IGF-1. Insulin and Growth Hormone have their own specific storage vesicles within specialize cells or tissue where they may sit and await a command for release. IGF-1 has no such storage compartment. Stated succinctly, Growth Hormone and Insulin are held in storage compartments before release whereas there is no such storage compartment for IGF-1.
This distinction has the consequence that circulating growth hormone and insulin are low under non-stimulated conditions. As a result the signal to the body to go on and do something as a command from growth hormone or insulin derives almost exclusively from controlling the entry rate of those peptide hormones into circulation. When these peptides can be coaxed from their storage areas into circulation they have the opportunity to transmit that signal or command to target tissue. As a consequence of having their own specific storage sites, the signal level that growth hormone is capable of bringing or the signal level that insulin is capable of bringing is primarily regulated by controlling their entry into circulation. It is not controlled by their rate of synthesis.
The synthesis of insulin and growth hormone need not be rapid. The concentration of these two hormones released into circulation is not limited by their rate of synthesis. The body seems to always have plenty at the ready. Enhancement of growth hormone or insulin synthesis is never something we need be immediately concerned.
The signaling commands that insulin and growth hormone bring are only effective if target cells express specific receptors to receive the hormones and capture that signal. So it is rapid changes in hormone concentration together with receptive tissue that initiates the body to do something.
All of this is distinct from the IGF-1 system. There is no gland or storage vesicle for IGF-1. Without a storage component housing complete and ready for release IGF-1, it becomes more dependent on various components to convey it's signaling command. The synthesis rate is important and IGF-1's appearance in circulation is slow and dependent on it's synthesis rate and on how the body chooses to maintain, discard or deliver it.
For IGF-1 the circulation becomes the extracellular storage area and it is maintained, discarded or delivered based on it's attachment to binding proteins or the ternary complex - Acid labile subunit. These binding proteins and the ternary complex are in a way virtual storage compartments as they maintain IGF-1. The total serum level of IGF-1 depends on both the synthesis rate and the capacity and stability of the aforementioned complexes which act as a buffer.
Growth hormone and Insulin are transmitted to target tissue in a pulse through the bloodstream from their storage units. The bloodstream is merely a means of transmission. For IGF-1 it must rely on the bloodstream to serve as it's reservoir.
IGF-1 also differs from growth hormone and insulin in that IGF-1 is produced in tissue throughout the body from muscle to brain (even though the liver remains the primary source). As a consequence IGF-1 is best thought of as an autocrine or paracrine IGF1 system even though circulating IGF-1 is often characterizes as endocrine or systemic. In the IGF-1 autocrine/paracrine system local signaling is highly dependent on the local synthesis and release of IGF acting on the producer cell, or its neighbours, by local diffusion. Furthermore local production of specific binding proteins may attract circulating IGF-1 and sequester them, either localizing them to target cells or retaining them in the producer tissue in an extracellular pool from which that cell population may eventually draw from. Proteases which cut off the IGF-1 from the attached binding proteins would free IGF-1 and make them available to the cellular receptors. The appearance of proteases to do this most likely comes from release & activation from damaged cells such as damaged muscle cells from resistance exercise.
IGF-1 once cut off from the local binding protein could either join a local pool of free IGF-1 for local activity or escape the local environment and enter circulation. Binding proteins in circulation would reattach to and buffer the paracrine IGF-1 to prevent the locally generated IGF-1 signaling to spread to other tissues.
Blood tests for circulating IGF-1 do not measure the activity of IGF-1. They are actually measuring the storage reserve. Whereas blood tests for growth hormone and insulin need to be timed correctly they do not measure storage but reveal the amount of peptide in route to activity at that point in time.
Here is an image and description created by Iain C.A.F. Robinson, Division of Molecular Neuroendocrinology MRC, National Institute for Medical Research, MillHill, London which helps make the storage distinction.
Endocrine vs paracrine secretory systems. a) The classical endocrine system, with a gland reserve of hormone and transmission of bursts of hormone release in the bloodstream to stimulate target tissues that selectively express the relevant hormone receptor. b) The endocrine IGF1 system has no primary gland store, but the peptide is constitutively produced from many tissues, with liver being a major source. The bloodstream serves as the IGF reservoir, retaining IGF1 complexed with binding proteins (BPs) and acid labile subunit (ALS) to prevent rapid elimination. A small proportion of free IGF dissociated from these complexes can bind IGF receptors in the target tissues. c) IGF1 is also generated locally in many tissues which are also targets for its action. They also produce binding proteins which may block or enhance IGF1 local action. BP and ALS in the circulation now serve to capture and buffer any locally produced IGF1 escaping to signal elsewhere.
To be continued... if there's an interestLast edited by DatBtrue; 2nd May 2016 at 06:26 PM.
IGF-1 - Primer part 2
IGF-1 as a regulator of Skeletal Muscle Hypertrophy and Atrophy
Let's start simply. Hypertrophy results from an enlargement. It is an increase in the size of something that exists and in regard to hypertrophy in skeletal muscle it is simply an increase in the size of existing muscle fibers. Hypertrophy does not refer to an increase in the number of pre-existing muscle fibers. IGF-1 is pro-hypertrophy meaning it promotes hypertrophy. It can play a role in the rare occurrence of hyperplasia which is an increase in the number of pre-existing muscle fibers. However most muscle mass increases in everyone from professional bodybuilders to the weekend hobbiest comes from hypertrophy so much so that hyperplasia is best left out of the anabolic discussion. Most people like the sound of the word "hyperplasia" but it is hypertrophy that does all the heavy lifting.
When free IGF-1 or rather the mature form of IGF-1 binds to it's receptor it triggers a series of events within a cell. This series is called signaling and the path that the signal takes is called a pathway. There are many components or elements within a cell that are capable of impacting that signal. These elements can play the role of handing the signal off to another element or they could somehow be an element that takes into consideration some sort of state... maybe a nutritional state... so they are in a way sensors... and based on what they sense about some state decide between which fork in the pathway the signal should be transmitted. Some elements amplify the signal. Some elements may inhibit the signal. Some elements play a small role while other play a huge role. The ones that play the huge role often receive the signal and based on that initiate events that will lead to gene transcription. Most elements in a cell aren't even called upon to play a part in a signaling cascade while some show up repeatedly in many varied contexts. Last but not least an element may be capable of residing in both the cytoplasm and nucleus and based on where it is currently residing activates distinct functions. Maybe if it is in the nucleus it is promoting but if it is in the cytoplasm it is inhibiting the signaling.
Again a pathway is a series of these elements and as a collective they are studied.
IGF-1's pro-hypertrophy activity primarily emanates from its ability to activate the Phosphoinositide 3-kinase (PI3k)/Akt signaling pathway. The introduction of names for our elements need not confuse. PI3k is an element and so is Akt. The pathway flows fromIGF-1 binding to it's receptor and triggering PI3k which transfers the signaling to Akt. Now there are minor elements between these two but they are the major elements and so the pathway is named after them. Here's what that portion of the signaling pathway looks like:
PI3K.Akt.jpg
Akt is a very important element. It can trigger protein synthesis and at the same time block up-regulation of the key mediators of muscle atrophy - MuRF1 and MAFbx . It triggers protein synthesis more directly by signaling to mTOR.
AKT-mTOR.jpg
It does the latter (prevention of atrophy) by preventing FOXO from moving to the nucleus and this has the ultimate effect of blocking the up-regulation of those muscle atrophy elements MuRF1 and MAFbx. MuRF1 and MAFbx cause atrophy by "spray painting" parts of proteins so that proteasomes can locate those areas and degrade the protein.
FOXO.jpg
When trying to understand things very simply it is best not to deviate but an intermediate deviation into FOXO can be found at post #17 in ARTICLE: Trying to write a simple understandable article - DAT) Mitochondria Biogenesis (picking thru material). Earlier I mentioned that some elements act as sensors and FOXO is one of them. From the above link
.Under normal growth conditions, FOXOs are inactivated and not required for the survival of cells.
Growth factors (such as insulin & IGF-1) inhibit FOXO activation whereas ROS, DNA-damage, energy stress activate it
It's an interesting post I made at that link. The point I appeared to be making is that there are some signals through FOXO that I want and some that I may not want. There is no inherent good or bad in inhibiting FOXO. Stopping FOXO from excessively triggering the atrophy of my muscles is good. Stopping FOXO so that things that need to be eliminated aren't isn't a good thing. That thread by the way is worth a glance... I tried very hard especially in the first page or 2 to make the topic very understandable.
ROZ.jpg
So back to the main thread... MuRF1 is really good at marking the thick muscle fibers for destruction and so by blocking MuRF1 activation IGF-1 through trigger Akt helps prevent the break down of the thicker parts of muscle.
IGF-1 may also strongly inhibit the anti-hypertrophy effects of myostatin. Myostatin activates two elements Smad2 and Smad3. It actually binds to a receptor complex made up of ACTRII and ALK4 or ALK5 and in so doing activates Smad2 and Smad3. Once activated these two move to the nucleus and from there they are able to inhibit Akt which ends up inhibiting TORC1. This inhibition feeds back and allows myostatin to activate even more Smad2. Akt remember does two things. It promotes protein synthesis through mTOR and it inhibits atrophy. When it does this in myoblast and myotubes this promotes anabolism and muscle mass. When Myostatin inhibits the activation of Akt in myoblasts and myotubes it hinders anabolism and muscle mass. To some extent TGFB may also activate SMAD2 & 3.
Now the signaling pathway Akt/mTOR/p70S6 in addition to increasing protein synthesis also mediates both differentiation in myoblasts and hypertrophy in myotubes.... basically the making and enlarging of muscle. If left to it's own devices myostatin would cause decreases in the diameters of myotubes.
IGF-1 dominantly blocks the effects of myostatin in myoblasts and myotubes. I didn't make up the word "dominate" it was used by the authors of Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size, Anne Ulrike Trendelenbur, American Journal of Physiology - Cell Physiology Published 1 June 2009 Vol. 296 no. 6, C1258-C1270 :
.Treatment of human myoblasts with myostatin for 24h decreased phosphorylation [i.e. activation] of Akt by up to 50%. In addition to inhibiting Akt, myostatin decreased phosphorylation of p70S6 kinase and the pro-atrophy transcription factor FoxO1, both of which are normally phosphorylated by Akt. However, Akt, p70S6 kinase, and FoxO1 phosphorylation were restored by treatment with IGF-1, indicating that IGF-1/Akt signaling is dominant over myostatin/Smad/Akt inhibition.
The authors also mentioned in partially non-published data that "In addition to restoring Akt phosphorylation, IGF-1 also partially rescues the differentiation of myostatin-treated myoblasts, as determined by measuring fusion index, diameters (data not shown), and CK (Creatine kinase) activity."
Total.jpg
So IGF-1 gets this signaling pathway going by stimulating PI3k/Akt which leads to the elements that can induce protein synthesis. It is a serious over simplification but resistance exercise leads to activation of the PI3k/Akt pathway by directly inducing muscle expression of IGF-1. - DeVol DL, Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth, Am J Physiol 259:E89–95 1990 & Yan Z, Insulin-like growth factor immunoreactivity increases in muscle after acute eccentric contractions, J Appl Physiol 74:410–414 1993 . This is sufficient to induce hypertrophy in muscle both in vitro - Vandenburgh HH, Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture, Am J Physiol 260:C475–484 1991 and later in vivo - Musaro A, Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle, Nature Genet 27:195–200 2001 & Coleman ME,Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice, J Biol Chem 270:12109–12116 1995
Activation of Akt is sufficient to induce hypertrophy in vivo. In the study cited for this sentence, acute activation of Akt for two to three weeks was found to be sufficient to induce a doubling in the size of skeletal muscle... this increase occurred in the average cross-sectional are of individual muscle fibers brought about by an increase in the TORC1/p70S6K protein synthesis pathways. - Lai K-MV, Conditional activation of Akt in adult skeletal muscle induces rapid hypertrophy, Mol Cell Biol 24:9295–9304 2004.
I should note that although IGF-1 activates mTOR and p70S6k downstream of PI3K/Akt activation, amino acids can activate mTOR directly bringing about a subsequent stimulation of p70S6K activity. For a much more detailed thread on this take a look at my writing in-> Regulation of muscle protein synthesis in humans
As part of that discussion in this thread Eukaryotic initiation factor 2B epsilon (eIF2Be) I discuss how important the element eIF2B is to protein synthesis and how GSK3beta blocks eIF2Bs activity. Well if GSK3beta is inhibited there is also enhanced myotube formation and muscle-specific gene expression leading to differentiation.
Although all of this may seem to be a bit much for this post I bring it up only to point out that IGF-1 inhibits GSK3beta which is a different mechanism by which hypertrophy is induced and myoblast differentiation promoted.
To be continued... but I think I have given a sufficient little primer on IGF-1 and intracellular signaling. IGF-1 is anabolic and anti-catabolic. It inhibits myostatin and GSK3beta and promotes both protein synthesis and differentiation.
In summation you now should have a cursory understanding of what is noted in blue on the flow chart below. The area denoted by green is some of what is discussed at the lengths above and is what BigEasy was trying to get at in his approach to using a limited amount of Essential Amino Acids.
So my next post will move away from this specific topic...
Good read.[h=2]GF-1, GHRP, Testosterone, Trenbolone & Nandrolone Primer [entire thread...] (What you should read if you don't want to be a beginner)[/h]I think it's important to start off by visualizing an interesting distinction between peptide hormones such as insulin and growth hormone and the peptide hormone IGF-1. Insulin and Growth Hormone have their own specific storage vesicles within specialize cells or tissue where they may sit and await a command for release. IGF-1 has no such storage compartment. Stated succinctly, Growth Hormone and Insulin are held in storage compartments before release whereas there is no such storage compartment for IGF-1.
This distinction has the consequence that circulating growth hormone and insulin are low under non-stimulated conditions. As a result the signal to the body to go on and do something as a command from growth hormone or insulin derives almost exclusively from controlling the entry rate of those peptide hormones into circulation. When these peptides can be coaxed from their storage areas into circulation they have the opportunity to transmit that signal or command to target tissue. As a consequence of having their own specific storage sites, the signal level that growth hormone is capable of bringing or the signal level that insulin is capable of bringing is primarily regulated by controlling their entry into circulation. It is not controlled by their rate of synthesis.
The synthesis of insulin and growth hormone need not be rapid. The concentration of these two hormones released into circulation is not limited by their rate of synthesis. The body seems to always have plenty at the ready. Enhancement of growth hormone or insulin synthesis is never something we need be immediately concerned.
The signaling commands that insulin and growth hormone bring are only effective if target cells express specific receptors to receive the hormones and capture that signal. So it is rapid changes in hormone concentration together with receptive tissue that initiates the body to do something.
All of this is distinct from the IGF-1 system. There is no gland or storage vesicle for IGF-1. Without a storage component housing complete and ready for release IGF-1, it becomes more dependent on various components to convey it's signaling command. The synthesis rate is important and IGF-1's appearance in circulation is slow and dependent on it's synthesis rate and on how the body chooses to maintain, discard or deliver it.
For IGF-1 the circulation becomes the extracellular storage area and it is maintained, discarded or delivered based on it's attachment to binding proteins or the ternary complex - Acid labile subunit. These binding proteins and the ternary complex are in a way virtual storage compartments as they maintain IGF-1. The total serum level of IGF-1 depends on both the synthesis rate and the capacity and stability of the aforementioned complexes which act as a buffer.
Growth hormone and Insulin are transmitted to target tissue in a pulse through the bloodstream from their storage units. The bloodstream is merely a means of transmission. For IGF-1 it must rely on the bloodstream to serve as it's reservoir.
IGF-1 also differs from growth hormone and insulin in that IGF-1 is produced in tissue throughout the body from muscle to brain (even though the liver remains the primary source). As a consequence IGF-1 is best thought of as an autocrine or paracrine IGF1 system even though circulating IGF-1 is often characterizes as endocrine or systemic. In the IGF-1 autocrine/paracrine system local signaling is highly dependent on the local synthesis and release of IGF acting on the producer cell, or its neighbours, by local diffusion. Furthermore local production of specific binding proteins may attract circulating IGF-1 and sequester them, either localizing them to target cells or retaining them in the producer tissue in an extracellular pool from which that cell population may eventually draw from. Proteases which cut off the IGF-1 from the attached binding proteins would free IGF-1 and make them available to the cellular receptors. The appearance of proteases to do this most likely comes from release & activation from damaged cells such as damaged muscle cells from resistance exercise.
IGF-1 once cut off from the local binding protein could either join a local pool of free IGF-1 for local activity or escape the local environment and enter circulation. Binding proteins in circulation would reattach to and buffer the paracrine IGF-1 to prevent the locally generated IGF-1 signaling to spread to other tissues.
Blood tests for circulating IGF-1 do not measure the activity of IGF-1. They are actually measuring the storage reserve. Whereas blood tests for growth hormone and insulin need to be timed correctly they do not measure storage but reveal the amount of peptide in route to activity at that point in time.
Here is an image and description created by Iain C.A.F. Robinson, Division of Molecular Neuroendocrinology MRC, National Institute for Medical Research, MillHill, London which helps make the storage distinction.
[FONT="]Endocrine vs paracrine secretory systems. a) The classical endocrine system, with a gland reserve of hormone and transmission of bursts of hormone release in the bloodstream to stimulate target tissues that selectively express the relevant hormone receptor. b) The endocrine IGF1 system has no primary gland store, but the peptide is constitutively produced from many tissues, with liver being a major source. The bloodstream serves as the IGF reservoir, retaining IGF1 complexed with binding proteins (BPs) and acid labile subunit (ALS) to prevent rapid elimination. A small proportion of free IGF dissociated from these complexes can bind IGF receptors in the target tissues. c) IGF1 is also generated locally in many tissues which are also targets for its action. They also produce binding proteins which may block or enhance IGF1 local action. BP and ALS in the circulation now serve to capture and buffer any locally produced IGF1 escaping to signal elsewhere.[/FONT]
To be continued... if there's an interest
Last edited by DatBtrue; 2nd May 2016 at 06:26 PM.
[h=2]IGF-1 - Primer part 2[/h]IGF-1 as a regulator of Skeletal Muscle Hypertrophy and Atrophy
Let's start simply. Hypertrophy results from an enlargement. It is an increase in the size of something that exists and in regard to hypertrophy in skeletal muscle it is simply an increase in the size of existing muscle fibers. Hypertrophy does not refer to an increase in the number of pre-existing muscle fibers. IGF-1 is pro-hypertrophy meaning it promotes hypertrophy. It can play a role in the rare occurrence of hyperplasia which is an increase in the number of pre-existing muscle fibers. However most muscle mass increases in everyone from professional bodybuilders to the weekend hobbiest comes from hypertrophy so much so that hyperplasia is best left out of the anabolic discussion. Most people like the sound of the word "hyperplasia" but it is hypertrophy that does all the heavy lifting.
When free IGF-1 or rather the mature form of IGF-1 binds to it's receptor it triggers a series of events within a cell. This series is called signaling and the path that the signal takes is called a pathway. There are many components or elements within a cell that are capable of impacting that signal. These elements can play the role of handing the signal off to another element or they could somehow be an element that takes into consideration some sort of state... maybe a nutritional state... so they are in a way sensors... and based on what they sense about some state decide between which fork in the pathway the signal should be transmitted. Some elements amplify the signal. Some elements may inhibit the signal. Some elements play a small role while other play a huge role. The ones that play the huge role often receive the signal and based on that initiate events that will lead to gene transcription. Most elements in a cell aren't even called upon to play a part in a signaling cascade while some show up repeatedly in many varied contexts. Last but not least an element may be capable of residing in both the cytoplasm and nucleus and based on where it is currently residing activates distinct functions. Maybe if it is in the nucleus it is promoting but if it is in the cytoplasm it is inhibiting the signaling.
Again a pathway is a series of these elements and as a collective they are studied.
IGF-1's pro-hypertrophy activity primarily emanates from its ability to activate the Phosphoinositide 3-kinase (PI3k)/Akt signaling pathway. The introduction of names for our elements need not confuse. PI3k is an element and so is Akt. The pathway flows fromIGF-1 binding to it's receptor and triggering PI3k which transfers the signaling to Akt. Now there are minor elements between these two but they are the major elements and so the pathway is named after them. Here's what that portion of the signaling pathway looks like:
PI3K.Akt.jpg
Akt is a very important element. It can trigger protein synthesis and at the same time block up-regulation of the key mediators of muscle atrophy - MuRF1 and MAFbx . It triggers protein synthesis more directly by signaling to mTOR.
AKT-mTOR.jpg
It does the latter (prevention of atrophy) by preventing FOXO from moving to the nucleus and this has the ultimate effect of blocking the up-regulation of those muscle atrophy elements MuRF1 and MAFbx. MuRF1 and MAFbx cause atrophy by "spray painting" parts of proteins so that proteasomes can locate those areas and degrade the protein.
FOXO.jpg
When trying to understand things very simply it is best not to deviate but an intermediate deviation into FOXO can be found at post #17 in ARTICLE: Trying to write a simple understandable article - DAT) Mitochondria Biogenesis (picking thru material). Earlier I mentioned that some elements act as sensors and FOXO is one of them. From the above link
.Under normal growth conditions, FOXOs are inactivated and not required for the survival of cells.
Growth factors (such as insulin & IGF-1) inhibit FOXO activation whereas ROS, DNA-damage, energy stress activate it
It's an interesting post I made at that link. The point I appeared to be making is that there are some signals through FOXO that I want and some that I may not want. There is no inherent good or bad in inhibiting FOXO. Stopping FOXO from excessively triggering the atrophy of my muscles is good. Stopping FOXO so that things that need to be eliminated aren't isn't a good thing. That thread by the way is worth a glance... I tried very hard especially in the first page or 2 to make the topic very understandable.
ROZ.jpg
So back to the main thread... MuRF1 is really good at marking the thick muscle fibers for destruction and so by blocking MuRF1 activation IGF-1 through trigger Akt helps prevent the break down of the thicker parts of muscle.
IGF-1 may also strongly inhibit the anti-hypertrophy effects of myostatin. Myostatin activates two elements Smad2 and Smad3. It actually binds to a receptor complex made up of ACTRII and ALK4 or ALK5 and in so doing activates Smad2 and Smad3. Once activated these two move to the nucleus and from there they are able to inhibit Akt which ends up inhibiting TORC1. This inhibition feeds back and allows myostatin to activate even more Smad2. Akt remember does two things. It promotes protein synthesis through mTOR and it inhibits atrophy. When it does this in myoblast and myotubes this promotes anabolism and muscle mass. When Myostatin inhibits the activation of Akt in myoblasts and myotubes it hinders anabolism and muscle mass. To some extent TGFB may also activate SMAD2 & 3.
Now the signaling pathway Akt/mTOR/p70S6 in addition to increasing protein synthesis also mediates both differentiation in myoblasts and hypertrophy in myotubes.... basically the making and enlarging of muscle. If left to it's own devices myostatin would cause decreases in the diameters of myotubes.
IGF-1 dominantly blocks the effects of myostatin in myoblasts and myotubes. I didn't make up the word "dominate" it was used by the authors of Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size, Anne Ulrike Trendelenbur, American Journal of Physiology - Cell Physiology Published 1 June 2009 Vol. 296 no. 6, C1258-C1270 :
.Treatment of human myoblasts with myostatin for 24h decreased phosphorylation [i.e. activation] of Akt by up to 50%. In addition to inhibiting Akt, myostatin decreased phosphorylation of p70S6 kinase and the pro-atrophy transcription factor FoxO1, both of which are normally phosphorylated by Akt. However, Akt, p70S6 kinase, and FoxO1 phosphorylation were restored by treatment with IGF-1, indicating that IGF-1/Akt signaling is dominant over myostatin/Smad/Akt inhibition.
The authors also mentioned in partially non-published data that "In addition to restoring Akt phosphorylation, IGF-1 also partially rescues the differentiation of myostatin-treated myoblasts, as determined by measuring fusion index, diameters (data not shown), and CK (Creatine kinase) activity."
Total.jpg
So IGF-1 gets this signaling pathway going by stimulating PI3k/Akt which leads to the elements that can induce protein synthesis. It is a serious over simplification but resistance exercise leads to activation of the PI3k/Akt pathway by directly inducing muscle expression of IGF-1. - [FONT="]DeVol DL, Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth, Am J Physiol 259:E89–95 1990 & Yan Z, Insulin-like growth factor immunoreactivity increases in muscle after acute eccentric contractions, J Appl Physiol 74:410–414 1993 [/FONT]. This is sufficient to induce hypertrophy in muscle both in vitro - [FONT="]Vandenburgh HH, Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture, Am J Physiol 260:C475–484 1991[/FONT] and later in vivo - [FONT="]Musaro A, Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle, Nature Genet 27:195–200 2001 & Coleman ME,Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice, J Biol Chem 270:12109–12116 1995[/FONT]
Activation of Akt is sufficient to induce hypertrophy in vivo. In the study cited for this sentence, acute activation of Akt for two to three weeks was found to be sufficient to induce a doubling in the size of skeletal muscle... this increase occurred in the average cross-sectional are of individual muscle fibers brought about by an increase in the TORC1/p70S6K protein synthesis pathways. - Lai K-MV, Conditional activation of Akt in adult skeletal muscle induces rapid hypertrophy, Mol Cell Biol 24:9295–9304 2004.
I should note that although IGF-1 activates mTOR and p70S6k downstream of PI3K/Akt activation, amino acids can activate mTOR directly bringing about a subsequent stimulation of p70S6K activity. For a much more detailed thread on this take a look at my writing in-> Regulation of muscle protein synthesis in humans
As part of that discussion in this thread Eukaryotic initiation factor 2B epsilon (eIF2Be) I discuss how important the element eIF2B is to protein synthesis and how GSK3beta blocks eIF2Bs activity. Well if GSK3beta is inhibited there is also enhanced myotube formation and muscle-specific gene expression leading to differentiation.
Although all of this may seem to be a bit much for this post I bring it up only to point out that IGF-1 inhibits GSK3beta which is a different mechanism by which hypertrophy is induced and myoblast differentiation promoted.
[FONT="]To be continued...[/FONT] but I think I have given a sufficient little primer on IGF-1 and intracellular signaling. IGF-1 is anabolic and anti-catabolic. It inhibits myostatin and GSK3beta and promotes both protein synthesis and differentiation.
In summation you now should have a cursory understanding of what is noted in blue on the flow chart below. The area denoted by green is some of what is discussed at the lengths above and is what BigEasy was trying to get at in his approach to using a limited amount of Essential Amino Acids.
So my next post will move away from this specific topic...
Agree.
