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Androgen Receptor
The androgen receptor is a type of nuclear receptor that is activated by binding any of the androgenic hormones. This includes test and DHT, in the cytoplasm (material in a eukaryotic or prokaryotic cell that is enclosed by the cell membrane) and then translocating to the nucleus.
The main function of the androgen receptor is as a DNA binding transcription factor that regulates gene expression. However it has other functions including development and upkeep of male sexual phenotype
Testosterone is an agonist (chemical that activates a receptor to produce a biological response) of the androgen receptor (AR). The AR is the biological target of endogenous test and DHT. This androgen binding results in the transcriptional regulation of a number of genes via androgen responsive elements. Upon binding to androgens, the AR dissociates from accessory proteins, translocates to the nucleus, dimerizes and then stimulates transcription of androgen responsive genes.
ARs also interact with other proteins in the nucleus which leads to up or down regulation of specific gene transcription. Up regulation results in increased synthesis of messenger RNA (mRNA) which is then translated by ribosomes (ribonucleoprotein responsible for synthesis of proteins) to produce certain proteins.
How Testosterone’s Molecule Shape Plays a Role
The shape of the test molecule significantly influences its binding affinity to the AR. When looking at 3D models of both the AR and the testosterone molecule we can see that their structures are meant for each other. Test fits precisely into the ligand binding domain (LBD) of the AR. Think of it like a key going into a lock. This induces a structural shift that locks the AR into an active mode, allowing it to regulate gene transcription.
AR Pathway Simplified
So basically, testosterone enters the androgen target cell and binds to the AR (will bind to AR after converting to DHT if 5AR is present).
Upon binding to the AR, it dissociates from chaperone protein complexes (heat shock proteins) in the cytoplasm.
This is simultaneously accompanied by conformational change of the receptor protein which leads to transformation and translocation to the nucleus.
When in the nucleus it binds as a homodimer to specific DNA elements present as enhanced upstream of androgen target genes.
They recruit coactivators which is what forms bridges of communication between the receptor and several components of the gene transcription.
This communication then triggers subsequent mRNA synthesis and consequently protein synthesis which results in androgenic responses.
mARs
mARs or membrane androgen receptors are a group of G protein coupled receptors that get activated by androgens. These work differently from traditional ARs. They are way faster in delivering their effects because they trigger non genomic cascades. Basically all that means is that it doesn't involve direct change in gene expression. Instead it just activates existing proteins or kinases. This is what makes these pathways faster.
Genomic and non genomic effects in muscle
Genomic refers to the binding of androgens to the androgen receptor that then translocates to the nucleus where it binds to AREs to signal different genes on and off to produce an effect, basically the pathway that alters gene transcription. Genomic pathways take a lot longer to exert their effects compared to non genomic pathways. Now looking at non genomic pathways, these get activated by androgens via the mAR or in the cytoplasm basically all it does is activate proteins and kinases to produce a biological effect. These pathways don't work through gene transcription. They also happen at a way faster rate than genomic pathways.
Polyamine Biosynthesis
Polyamines are molecules that help cells proliferate and differentiate. (These molecules include spermine, spermidine, and putrescine). When muscle hypertrophies its associated with increased polyamine levels. Also when muscle atrophies it is associated with decreased polyamine levels.
(Rat studies)
So now we see their part in skeletal muscle. Androgens may contribute to this because they can directly regulate polyamine biosynthesis through upregulation of the rate limiting biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase, encoded by the genes Odc1 and Amd1. Male rats that got their balls removed showed a decrease in these genes that were then regenerated with testosterone treatment. Another decrease of these genes were also seen in androgen receptor knockout (ARKO) mice. This suggests that androgens can upregulate these genes which upregulates the enzymes I mentioned earlier. This is an example of a genomic effect because they upregulate the Odc1 and Amd1 gene.
Satellite Cells
When a muscle grows, satellite cells activate. Once activated they proliferate, these myoblasts then differentiate into myocytes that fuse to make myotubes with multiple nuclei. These then turn into muscle fibers which obviously means muscle hypertrophy. They're basically just muscle stem cells. Satellite cells and myonuclei are the predominant sites of AR expression in muscle tissue. Supraphysiological amounts of Androgens can cause these to proliferate a lot more leading to more muscle hypertrophy.
What's interesting is that there are more cells that express ARs (pluripotent mesenchymal precursor cells and motoneurons) that may potentially contribute to muscle hypertrophy as well. This is up for debate though and will need more studies conducted.
Unfinished
The androgen receptor is a type of nuclear receptor that is activated by binding any of the androgenic hormones. This includes test and DHT, in the cytoplasm (material in a eukaryotic or prokaryotic cell that is enclosed by the cell membrane) and then translocating to the nucleus.
The main function of the androgen receptor is as a DNA binding transcription factor that regulates gene expression. However it has other functions including development and upkeep of male sexual phenotype
Testosterone is an agonist (chemical that activates a receptor to produce a biological response) of the androgen receptor (AR). The AR is the biological target of endogenous test and DHT. This androgen binding results in the transcriptional regulation of a number of genes via androgen responsive elements. Upon binding to androgens, the AR dissociates from accessory proteins, translocates to the nucleus, dimerizes and then stimulates transcription of androgen responsive genes.
ARs also interact with other proteins in the nucleus which leads to up or down regulation of specific gene transcription. Up regulation results in increased synthesis of messenger RNA (mRNA) which is then translated by ribosomes (ribonucleoprotein responsible for synthesis of proteins) to produce certain proteins.
How Testosterone’s Molecule Shape Plays a Role
The shape of the test molecule significantly influences its binding affinity to the AR. When looking at 3D models of both the AR and the testosterone molecule we can see that their structures are meant for each other. Test fits precisely into the ligand binding domain (LBD) of the AR. Think of it like a key going into a lock. This induces a structural shift that locks the AR into an active mode, allowing it to regulate gene transcription.
AR Pathway Simplified
So basically, testosterone enters the androgen target cell and binds to the AR (will bind to AR after converting to DHT if 5AR is present).
Upon binding to the AR, it dissociates from chaperone protein complexes (heat shock proteins) in the cytoplasm.
This is simultaneously accompanied by conformational change of the receptor protein which leads to transformation and translocation to the nucleus.
When in the nucleus it binds as a homodimer to specific DNA elements present as enhanced upstream of androgen target genes.
They recruit coactivators which is what forms bridges of communication between the receptor and several components of the gene transcription.
This communication then triggers subsequent mRNA synthesis and consequently protein synthesis which results in androgenic responses.
mARs
mARs or membrane androgen receptors are a group of G protein coupled receptors that get activated by androgens. These work differently from traditional ARs. They are way faster in delivering their effects because they trigger non genomic cascades. Basically all that means is that it doesn't involve direct change in gene expression. Instead it just activates existing proteins or kinases. This is what makes these pathways faster.
Genomic and non genomic effects in muscle
Genomic refers to the binding of androgens to the androgen receptor that then translocates to the nucleus where it binds to AREs to signal different genes on and off to produce an effect, basically the pathway that alters gene transcription. Genomic pathways take a lot longer to exert their effects compared to non genomic pathways. Now looking at non genomic pathways, these get activated by androgens via the mAR or in the cytoplasm basically all it does is activate proteins and kinases to produce a biological effect. These pathways don't work through gene transcription. They also happen at a way faster rate than genomic pathways.
Polyamine Biosynthesis
Polyamines are molecules that help cells proliferate and differentiate. (These molecules include spermine, spermidine, and putrescine). When muscle hypertrophies its associated with increased polyamine levels. Also when muscle atrophies it is associated with decreased polyamine levels.
(Rat studies)
So now we see their part in skeletal muscle. Androgens may contribute to this because they can directly regulate polyamine biosynthesis through upregulation of the rate limiting biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase, encoded by the genes Odc1 and Amd1. Male rats that got their balls removed showed a decrease in these genes that were then regenerated with testosterone treatment. Another decrease of these genes were also seen in androgen receptor knockout (ARKO) mice. This suggests that androgens can upregulate these genes which upregulates the enzymes I mentioned earlier. This is an example of a genomic effect because they upregulate the Odc1 and Amd1 gene.
Satellite Cells
When a muscle grows, satellite cells activate. Once activated they proliferate, these myoblasts then differentiate into myocytes that fuse to make myotubes with multiple nuclei. These then turn into muscle fibers which obviously means muscle hypertrophy. They're basically just muscle stem cells. Satellite cells and myonuclei are the predominant sites of AR expression in muscle tissue. Supraphysiological amounts of Androgens can cause these to proliferate a lot more leading to more muscle hypertrophy.
What's interesting is that there are more cells that express ARs (pluripotent mesenchymal precursor cells and motoneurons) that may potentially contribute to muscle hypertrophy as well. This is up for debate though and will need more studies conducted.
Unfinished
