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Many of us use androgenic compounds, but do we really understand how they work?
I know most of you will say that they boost protein synthesis, increasing muscular size and strength.
While this is true enough; it is a bit more complicated than that. I will try to give a simplified account of just how androgens really “work”.
Hormone Receptors
Androgens, just like many other types of hormones work by “binding” to receptors. You can think of the receptors as locks, and their corresponding hormones which activate them as “keys” which fit in the receptors in order to “unlock” or activate them. Receptors can be in the cell membrane or on the nucleus. The number of available receptors is an important limiting factor in regulating the activity of hormones. Most androgens work primarily by activating the AR (androgen receptor). In addition to the intended “key”, other compounds can also bind to the same receptors with differing effects.
Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently. Natural hormones are themselves agonists and, in many cases, more than one distinct hormone binds to the same receptor. For a given receptor, different agonists can have dramatically different potencies.
Antagonists are molecules that bind the receptor, but fail to trigger intracellular signalling events. By occupying or blocking the “key hole”, antagonists prevent the activating hormone from binding to its target receptor, preventing activation of the receptor, which reduces the effects of the hormone.
When any AAS compound binds to an androgen receptor, a unit called a “hormone-receptor complex” is formed. This HRC then enters the cell, and migrates to the cell nucleus where genetic transcription takes place. The primary mechanism of action of androgenic compounds is the modulation of gene expression, which just means that instructions are carried out to produce specific proteins. Nuclei are the cellular factories for producing proteins. DNA is only capable of producing different combinations of amino acids – proteins. All other cellular activity is then controlled by these proteins. The HRC binds to a specific sequence of DNA called a “hormone response element”, which results in increased messenger-RNA synthesis. The mRNA are transcribed by ribosomes to produce the specific proteins.
Instructions to transcribe the two primary contractile proteins, actin and myosin can be carried out. Increased synthesis of these contractile proteins increases a muscle cell's size and strength. Androgens can also enhance the synthesis of creatine, providing increased celullar energy for greater strength. Other messenger proteins, such as IGF-1 can also be produced in this same way; it actually turns out that estrogen plays an important role in both the production and expression of many growth factors. (Androgens can also suppress the synthesis of peptide binding proteins, like IGFBP-3, which also increases the activity of the corresponding peptide.)
Androgens can also displace cortisol (or other glucocorticoids) from their target receptors. By “antagonizing” the glucocorticoid receptor in this way, androgens reduce the catabolic effects of these hormones. (Androgens can also interfere with the function of the cortisol response element inside the nucleus.) In the kidneys, instructions can be carried out for the production of more Red Blood Cells, a process known as "erythropoiesis".
One of the more important effects of AAS is to increase AR density. Contrary to popular belief, AAS do not “down-regulate” the androgen receptors. In fact, they actually up-regulate the receptors, making cells more responsive to the effects of androgenic hormones. They do this primarily by instructing the cells to create more AR's. The greater the number of available AR's, the more responsive a given cell will be to the presence of androgens.
Since AAS is capable of increasing protein synthesis, why then is exercise even necessary?
With all of these effects of androgenic compounds, we still have not discussed the most important way in which anabolic compounds cause muscular growth. As already mentioned, the cellular nuclei are the “factories” for synthesizing protein. However, there is a limit to the amount of protein that can be produced by a given number of nuclei in a muscle cell. So, in order to further increase protein synthesis and muscle growth, there must be some way to either increase the number of muscle cells, or the number of nuclei in a given muscle cell.
Satellite Cells
As a result of the muscular “trauma” or damage that results from exercise, and a number of other complex factors beyond the scope of this discussion, myogenic stem cells, aka, satellite cells are activated. Anabolic compounds can promote the activation of these specialized cells which usually remain dormant. Once again this is accomplished by affecting genetic transciption. The enhanced activation of satellite cells is the most important way that anabolics promote muscle growth. Growth factors, like IGF-1, also play an important role in the activation and differentiation of satellite cells.
Once activated, satellite cells divide and multiply to form cells called “myoblasts”. These myoblasts then fuse with existing muscle fibers (called "myocytes") donating their nuclei. Increasing the number of nuclei allows myocytes to regulate a larger amount of cytoplasm, enabling cell growth, and greater protein synthesis. The ratio of the number of nuclei to cytoplasm volume in a muscle cell determines the type of “twitch”, either fast or slow, of the affected fiber. Slow-twitch fibers (also known as Type I muscle fibers) have approximately five times the number of satellite cells as fast-twitch muscle (Type II muscle fibers). The primary purpose of satellite cells is not to form new muscle fibers, but to add nuclei to existing fibers allowing for greater growth and protein synthesis. If you want to make more of something, i.e. protein, you first need more production factories, i.e. cellular nuclei. (Under special circumstances, however, satellite cells can form completely new muscle fiber, a process known as “hyperplasia”, as opposed to “hypertrophy”.)
Exercise and Inflammation
Aside from its effects on the satellite cells, muscle trauma also causes activation of the immune system, which leads to inflammation. One type of immune cell that becomes involved is called a macrophage, which works to remove debris from damaged cells and also secretes chemical signals, such as cytokines and growth factors. The growth factors stimulate the synthesis of new proteins in the muscle cells. The cytokines help activate and recruit the satellite cells, as well as cause other immune cells to come to the damaged muscle. These cells help repair the damaged muscle cells and break down unnecessary proteins, allowing the damaged cells to make new proteins that helps them get bigger and stronger.
written by VX1
I know most of you will say that they boost protein synthesis, increasing muscular size and strength.
While this is true enough; it is a bit more complicated than that. I will try to give a simplified account of just how androgens really “work”.
Hormone Receptors
Androgens, just like many other types of hormones work by “binding” to receptors. You can think of the receptors as locks, and their corresponding hormones which activate them as “keys” which fit in the receptors in order to “unlock” or activate them. Receptors can be in the cell membrane or on the nucleus. The number of available receptors is an important limiting factor in regulating the activity of hormones. Most androgens work primarily by activating the AR (androgen receptor). In addition to the intended “key”, other compounds can also bind to the same receptors with differing effects.
Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently. Natural hormones are themselves agonists and, in many cases, more than one distinct hormone binds to the same receptor. For a given receptor, different agonists can have dramatically different potencies.
Antagonists are molecules that bind the receptor, but fail to trigger intracellular signalling events. By occupying or blocking the “key hole”, antagonists prevent the activating hormone from binding to its target receptor, preventing activation of the receptor, which reduces the effects of the hormone.
When any AAS compound binds to an androgen receptor, a unit called a “hormone-receptor complex” is formed. This HRC then enters the cell, and migrates to the cell nucleus where genetic transcription takes place. The primary mechanism of action of androgenic compounds is the modulation of gene expression, which just means that instructions are carried out to produce specific proteins. Nuclei are the cellular factories for producing proteins. DNA is only capable of producing different combinations of amino acids – proteins. All other cellular activity is then controlled by these proteins. The HRC binds to a specific sequence of DNA called a “hormone response element”, which results in increased messenger-RNA synthesis. The mRNA are transcribed by ribosomes to produce the specific proteins.
Instructions to transcribe the two primary contractile proteins, actin and myosin can be carried out. Increased synthesis of these contractile proteins increases a muscle cell's size and strength. Androgens can also enhance the synthesis of creatine, providing increased celullar energy for greater strength. Other messenger proteins, such as IGF-1 can also be produced in this same way; it actually turns out that estrogen plays an important role in both the production and expression of many growth factors. (Androgens can also suppress the synthesis of peptide binding proteins, like IGFBP-3, which also increases the activity of the corresponding peptide.)
Androgens can also displace cortisol (or other glucocorticoids) from their target receptors. By “antagonizing” the glucocorticoid receptor in this way, androgens reduce the catabolic effects of these hormones. (Androgens can also interfere with the function of the cortisol response element inside the nucleus.) In the kidneys, instructions can be carried out for the production of more Red Blood Cells, a process known as "erythropoiesis".
One of the more important effects of AAS is to increase AR density. Contrary to popular belief, AAS do not “down-regulate” the androgen receptors. In fact, they actually up-regulate the receptors, making cells more responsive to the effects of androgenic hormones. They do this primarily by instructing the cells to create more AR's. The greater the number of available AR's, the more responsive a given cell will be to the presence of androgens.
Since AAS is capable of increasing protein synthesis, why then is exercise even necessary?
With all of these effects of androgenic compounds, we still have not discussed the most important way in which anabolic compounds cause muscular growth. As already mentioned, the cellular nuclei are the “factories” for synthesizing protein. However, there is a limit to the amount of protein that can be produced by a given number of nuclei in a muscle cell. So, in order to further increase protein synthesis and muscle growth, there must be some way to either increase the number of muscle cells, or the number of nuclei in a given muscle cell.
Satellite Cells
As a result of the muscular “trauma” or damage that results from exercise, and a number of other complex factors beyond the scope of this discussion, myogenic stem cells, aka, satellite cells are activated. Anabolic compounds can promote the activation of these specialized cells which usually remain dormant. Once again this is accomplished by affecting genetic transciption. The enhanced activation of satellite cells is the most important way that anabolics promote muscle growth. Growth factors, like IGF-1, also play an important role in the activation and differentiation of satellite cells.
Once activated, satellite cells divide and multiply to form cells called “myoblasts”. These myoblasts then fuse with existing muscle fibers (called "myocytes") donating their nuclei. Increasing the number of nuclei allows myocytes to regulate a larger amount of cytoplasm, enabling cell growth, and greater protein synthesis. The ratio of the number of nuclei to cytoplasm volume in a muscle cell determines the type of “twitch”, either fast or slow, of the affected fiber. Slow-twitch fibers (also known as Type I muscle fibers) have approximately five times the number of satellite cells as fast-twitch muscle (Type II muscle fibers). The primary purpose of satellite cells is not to form new muscle fibers, but to add nuclei to existing fibers allowing for greater growth and protein synthesis. If you want to make more of something, i.e. protein, you first need more production factories, i.e. cellular nuclei. (Under special circumstances, however, satellite cells can form completely new muscle fiber, a process known as “hyperplasia”, as opposed to “hypertrophy”.)
Exercise and Inflammation
Aside from its effects on the satellite cells, muscle trauma also causes activation of the immune system, which leads to inflammation. One type of immune cell that becomes involved is called a macrophage, which works to remove debris from damaged cells and also secretes chemical signals, such as cytokines and growth factors. The growth factors stimulate the synthesis of new proteins in the muscle cells. The cytokines help activate and recruit the satellite cells, as well as cause other immune cells to come to the damaged muscle. These cells help repair the damaged muscle cells and break down unnecessary proteins, allowing the damaged cells to make new proteins that helps them get bigger and stronger.
written by VX1