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IGF-1
I touched on IGF-1 (Insulin like growth factor 1) a little bit in the mTOR thread but this will be a deeper look into this hormone. IGF1 has a similar molecular structure to insulin. IGF1 is a part of the somatotropic axis (GH/IGF1). Testosterone amplifies this axis by enhancing the secretary pattern of GH, thus leading to more IGF1 production.
This of course leads to more hepatic secretion of igf1. However circulating levels of igf1 don't really do much in terms of muscle hypertrophy, its local form fills in that role.
Local igf1 mogs serum igf1 in regards to muscle hypertrophy. Testosterone produces local igf1 within skeletal muscle tissue. When testosterone enters its target cell in the muscle it will go through the typical genomic pathway and end up binding to AREs, from there it will upregulate the igf1 gene while also decreasing igfbp-4 which is an inhibitory protein. This causes more bioavailable, local igf1 right there in the muscle.
This local igf1 then can activate downstream cascades such as PI3K/akt/mTORC1, satellite cell proliferation, as well as interacting with GLUT4 and inhibiting catabolic pathways.
So igf1 binds to igf1 receptors in the muscle cell and then those activate PI3K/akt which then inhibits FoxO which leads to less protein degradation. It also activates mTORC1 via the same PI3K/akt pathway which mediates protein synthesis.
Igf is expressed in two forms. igf1Ea and igf1Ec (MGF). These are what's gonna influence your satellite cells. MGF influences myoblast proliferation while also inhibiting terminal differentiation in C2C12 myoblast cell line. IGF1Ea stimulates myoblast differentiation into myotubes. These two isoforms are actually observed to positively regulate β catenine. This means that it can inhibit myostatin nicely.
So with all of this catabolic inhibition, phosphorylation and gene expression it is evident that IGF1 plays a significant role in skeletal muscle hypertrophy.
PI3K/akt
Okay so we know that androgens interact with these proteins and induce muscle hypertrophy. Now let's look at it on a little bit of a deeper level, as I explained they activate these proteins either directly or from conversion into IGF1 and they phosphorylate downstream and activate the mTOR. However these phosphorylations can also inhibit forkhead box O (FoxO). FoxO is responsible for upregulating MuRF-1 and MAFbx. Basically these are ubiquitin ligases that are upregulated during muscle atrophy, they play key roles in skeletal muscle degradation which is obviously something we don't want. But as I said earlier, testosterone inhibits FoxO via PI3K/akt downstream phosphorylation thus leading to lower levels of MuRF-1 and MAFbx which means less muscle protein degradation.
Another downstream effect of androgens acting upon the PI3K/akt is notch signalling. Notch signalling is good for satellite cell proliferation.
Testosterone also inhibits c Jun NH2-terminal kinase (JNK) and also activates
MAPK. These two factors are good for notch signalling which then leads to better cell proliferation. Notch signalling can be activated directly via androgens or indirectly via PI3K/akt.
Myostatin Inhibition
Testosterone inhibits activity and expression of myostatin. Myostatin is a member of the transforming growth factor-β (TGF-β) super family that's expressed in skeletal muscle. It's basically like a brake for your muscle growth. It represses protein synthesis by inhibiting the PI3K/akt thus upregulating FoxO. It is also bad for myoblast proliferation and differentiation, thus limiting the amount of muscle you can build.
Myostatin is proposed to act on pluripotent mesenchymal precursor cells. This is because myostatin knockout mice were associated with decreased adipogenesis and body fat. Myostatin also induces the expression of adipogenic markers in the pluripotent mesenchymal cell line. Basically what this means is that the pluripotent mesenchymal cells can turn into either myocytes (muscle cells) or adipocytes (fat cells). Lower myostatin can help these cells turn into muscle.
Myostatin binds to activin receptors type 1 and 2 and upon tetramerization of the receptor complex the signal is sent to the cytoplasm via the SMAD proteins. The receptors phosphorylate the SMAD proteins. The phosphorylated SMAD4 will translocate to the nucleus and then regulate target genes, this is how myostatin regulates muscle degradation. A protein called follistatin antagonizes myostatin thus preventing it from binding to its receptor and downregulating its effects.
Testosterone inhibits myostatin by repressing the myostatin at a gene level, some sources also support the theory that androgens upregulate β catenin signalling which then upregulates follistatin which then inhibits myostatin. Speaking of β catenin, testosterone has been observed to downregulate axin which is a negative regulator of β catenin. This was observed in rats who were given exogenous testosterone because they couldn't produce their own because their balls were cut off. Of course with β catenin not being downregulated by axin, it can produce more follistatin and inhibit myostatin. Direct AR and β catenine interaction has also been observed before which may help against degradation.
Testosterone may also activate adenosine monophosphate-activated kinase (AMPK) which can lead to more β catenine stabilization.
I touched on IGF-1 (Insulin like growth factor 1) a little bit in the mTOR thread but this will be a deeper look into this hormone. IGF1 has a similar molecular structure to insulin. IGF1 is a part of the somatotropic axis (GH/IGF1). Testosterone amplifies this axis by enhancing the secretary pattern of GH, thus leading to more IGF1 production.
This of course leads to more hepatic secretion of igf1. However circulating levels of igf1 don't really do much in terms of muscle hypertrophy, its local form fills in that role.
Local igf1 mogs serum igf1 in regards to muscle hypertrophy. Testosterone produces local igf1 within skeletal muscle tissue. When testosterone enters its target cell in the muscle it will go through the typical genomic pathway and end up binding to AREs, from there it will upregulate the igf1 gene while also decreasing igfbp-4 which is an inhibitory protein. This causes more bioavailable, local igf1 right there in the muscle.
This local igf1 then can activate downstream cascades such as PI3K/akt/mTORC1, satellite cell proliferation, as well as interacting with GLUT4 and inhibiting catabolic pathways.
So igf1 binds to igf1 receptors in the muscle cell and then those activate PI3K/akt which then inhibits FoxO which leads to less protein degradation. It also activates mTORC1 via the same PI3K/akt pathway which mediates protein synthesis.
Igf is expressed in two forms. igf1Ea and igf1Ec (MGF). These are what's gonna influence your satellite cells. MGF influences myoblast proliferation while also inhibiting terminal differentiation in C2C12 myoblast cell line. IGF1Ea stimulates myoblast differentiation into myotubes. These two isoforms are actually observed to positively regulate β catenine. This means that it can inhibit myostatin nicely.
So with all of this catabolic inhibition, phosphorylation and gene expression it is evident that IGF1 plays a significant role in skeletal muscle hypertrophy.
PI3K/akt
Okay so we know that androgens interact with these proteins and induce muscle hypertrophy. Now let's look at it on a little bit of a deeper level, as I explained they activate these proteins either directly or from conversion into IGF1 and they phosphorylate downstream and activate the mTOR. However these phosphorylations can also inhibit forkhead box O (FoxO). FoxO is responsible for upregulating MuRF-1 and MAFbx. Basically these are ubiquitin ligases that are upregulated during muscle atrophy, they play key roles in skeletal muscle degradation which is obviously something we don't want. But as I said earlier, testosterone inhibits FoxO via PI3K/akt downstream phosphorylation thus leading to lower levels of MuRF-1 and MAFbx which means less muscle protein degradation.
Another downstream effect of androgens acting upon the PI3K/akt is notch signalling. Notch signalling is good for satellite cell proliferation.
Testosterone also inhibits c Jun NH2-terminal kinase (JNK) and also activates
MAPK. These two factors are good for notch signalling which then leads to better cell proliferation. Notch signalling can be activated directly via androgens or indirectly via PI3K/akt.
Myostatin Inhibition
Testosterone inhibits activity and expression of myostatin. Myostatin is a member of the transforming growth factor-β (TGF-β) super family that's expressed in skeletal muscle. It's basically like a brake for your muscle growth. It represses protein synthesis by inhibiting the PI3K/akt thus upregulating FoxO. It is also bad for myoblast proliferation and differentiation, thus limiting the amount of muscle you can build.
Myostatin is proposed to act on pluripotent mesenchymal precursor cells. This is because myostatin knockout mice were associated with decreased adipogenesis and body fat. Myostatin also induces the expression of adipogenic markers in the pluripotent mesenchymal cell line. Basically what this means is that the pluripotent mesenchymal cells can turn into either myocytes (muscle cells) or adipocytes (fat cells). Lower myostatin can help these cells turn into muscle.
Myostatin binds to activin receptors type 1 and 2 and upon tetramerization of the receptor complex the signal is sent to the cytoplasm via the SMAD proteins. The receptors phosphorylate the SMAD proteins. The phosphorylated SMAD4 will translocate to the nucleus and then regulate target genes, this is how myostatin regulates muscle degradation. A protein called follistatin antagonizes myostatin thus preventing it from binding to its receptor and downregulating its effects.
Testosterone inhibits myostatin by repressing the myostatin at a gene level, some sources also support the theory that androgens upregulate β catenin signalling which then upregulates follistatin which then inhibits myostatin. Speaking of β catenin, testosterone has been observed to downregulate axin which is a negative regulator of β catenin. This was observed in rats who were given exogenous testosterone because they couldn't produce their own because their balls were cut off. Of course with β catenin not being downregulated by axin, it can produce more follistatin and inhibit myostatin. Direct AR and β catenine interaction has also been observed before which may help against degradation.
Testosterone may also activate adenosine monophosphate-activated kinase (AMPK) which can lead to more β catenine stabilization.
