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Outgrowing Your Genes: Part II
By Greg Bradley-Popovich, DPT, MSEP, MS, CSCS
© 1999
Originally published in Exercise Protocol
Again we tread on, relentlessly beating back the brushfires of ignorance. This is the second article in a series that attempts to elucidate the mechanisms that play a role in determining "genetic potential" in body building. In other words, we're trying to bring to light that which ultimately limits your muscle growth despite your best and most logical resistance-training efforts.
EP makes every effort to make each article in a series independent so that it can stand on its own without relying on the previous articles. However, because of the complexity of the material presented herein, it may be helpful to review part one in this series.
All too often several accepted and official names exist for the same thing (e.g., "muscle cell" a.k.a "mucle fiber" a.k.a. "myofiber" a.k.a. "myocyte"). In this article, I will utilize all of the aformentioned synonyms. This will be done to annoy you. Seriously, I will use them interchangeably so that readers become familiar and comfortable with all of the terminology, and will not be limited by my personal bias. A goal of EP is to make both your muscles AND your mind grow.
In addition to the genetic material found within a muscle cell, as described in detail in part one, there also exists a virtual reservoir of genetic material residing just outside muscle cells in the form of nuclei within other nearby cells. Because of their peripheral relationship to muscle cells, these reservoirs of genetic material have been aptly named "satellite cells". Luckily, that is their only accepted name, as first given by Alexander Mauro in 1961 (4, 14). Much of our interest in muscle-building potential should probably revolve around satellite cells (pun intended).
(It is worth mentioning that the term "satellite cell" has not been usurped by those cells associated with muscle cells. In fact, the nervous system also possesses cells named satellite cells, though they are not functionally related to those in muscle tissue.)
With an electron microscope, satellite cells appear nestled against myocytes, yet are completely segregated by their own bilayered cell membrane as well as the cell membrane of the muscle cell. Satellite cells may reside in an indentation on the surface of the myocyte, or may be flattened, resulting in a little bump on the surface of the muscle fiber (15). Satellite cells were once simply thought to be spindle-shaped. Now it is recognized that they exhibit a complex morphology (i.e., structure), having many tiny radiating projections (22). Each muscle cell is associated with a few such satellite cells. Satellite cells have a single nucleus that occupies most of the cell's scanty cytoplasm (15). Contrast these little noncontractile cells to mighty myocytes which may have hundreds or even thousands of nuclei (4). The nuclei of satellite cells are simply referred to as "satellite cell nuclei". The nuclei within a muscle cell are called "true myonuclei" (4). All of the nuclei in and surrounding muscle cells (true myonuclei plus satellite cell nuclei) can be referred to generally as "total myonuclei". Some estimates of the total contribution of satellite cell nuclei to total myonuclei in adults vary from as little as 1 percent all the way up to 11 percent (15). However, it is safe to say that the total number of true myonuclei vastly outnumbers the sum of satellite cell nuclei.
Both the satellite cell and the myocyte are enveloped in a continuous connective tissue cobweb. This inner layer of connective tissue that surrounds each and every muscle cell is known as the endomysium (9). Presentation of this information is to facilitate understanding of the structure known as the "basement membrane" or "basal lamina" or "external lamina" (here we go again...), a structure frequently mentioned when discussing satellite cells.
The basement membrane refers to a thin extracellular matrix, which is by definition acellular (i.e., without cells) (9). It lies between the endomysium and the cell membrane of the myocyte (refer to accompanying diagram). The term basement membrane is often incorrectly used interchangeably with the term basal lamina; the basement membrane and the basal lamina are related, but NOT synonymous. Actually, the basement membrane consists of two layers, one of which IS the basal lamina immediately adjacent to the myocytic cell membrane. The other layer of the basement membrane is the reticular lamina, which connects to the endomysium (10). It IS accurate to use the terms basal lamina and external lamina interchangeably when referring to muscle tissue (9, 10). Perhaps surprisingly, it is actually the muscle cell that synthesizes the basal lamina (10), although we may not normally think of muscle cells as having a secretory function. Overall, the role of the basement membrane is to support the adjacent myocyte both structurally and physiologically.
At this point, you may be wondering what, if anything, the basement membrane has to do with the cellular regulation of muscle growth and your genetic potential. Well, if it weren't for the basement membrane, and particularly the basal lamina, satellite cells couldn't fulfill all of their functions. Now onto the meat of the article...
So what is so special about these satellite cells? Actually, without a stressor, satellite cells don't do a hell of a lot. They can ordinarily be considered quiescent, or dormant (4, 14, 15). But we body builders are extraordinary, and that's where satellite cells come into play.
Recall that skeletal muscle cells are postmitotic, meaning they cannot divide to increase in number. This is unfortunate, because if mature skeletal muscle cells could mitotically divide just once, you'd double your muscle mass! Since this is an impossibility, the body does the best it can through satellite cells. The salient quality of satellite cells is that they still possess the ability to divide (5). They are actually leftover muscle precursor cells capable of differentiating into cells referred to as myoblasts (15), a term which literally means "muscle formers".
The phenomenon of satellite cell recruitment is very complex. In addition to a mechanical stressor, the process is apparently influenced by a number of factors and hormones, including hepatocyte growth factor/scatter factor (8, 24), fibroblast growth factor (6), testosterone (12), insulin, insulin-like growth factor I, insulin-like growth factor II (7), and transforming growth factor-beta (1). (A brief explanation of the terms "factor" and "hormone" is warranted: "Often, use of the term 'factor' indicates that the chemical nature of the substance or its mechanism of action are unknown, as in endocrinology where 'factors' are known as 'hormones' when their chemical nature is determined" (25). ) Under the influence of these substances, satellite cell activation and division usually peaks within 1 to 3 days of the initial stressor, at least in small mammals (11, 18, 20).
As we shall see, satellite cells play not just a role in muscle hypertrophy, but also a crucial role in muscle regeneration. Let's begin with regeneration. When a muscle cell is torn, as with a forceful external impact (e.g., getting hit on the deltoid with a baseball) or with a muscle pull or tear, the muscle cell will likely die. In such situations, the basal lamina often persists after a traumatic insult to a muscle cell. So long as the nurturing basal lamina is intact, it serves as a scaffold to guide the regeneration of the muscle cell (10). This process of regeneration occurs by satellite cells immediately around the injured myocyte first mitotically dividing (proliferating), then migrating towards one another (15). The satellite cells are steered during migration to the site of injury by two chemotactic substances secreted by damaged muscle cells: hepatocyte growth factor and transforming growth factor-beta, both mentioned above (2). After migration, the satellite cells, already programmed to form a specific fiber type (13), proceed by differentiating into myoblasts. Then the myoblasts fuse to form what is known as a myotube (15), which eventually manufactures the necessary contractile proteins to become a full-fledged muscle cell. Alternatively, if the basal lamina is also severely disrupted, the muscle cell suffers necrosis (i.e., death), is permanently lost, and is replaced with connective tissue scarring as opposed to another muscle cell derived from satellite cells (10).
How are satellite cells related to muscle growth? Given the above scenario, when a muscle cell dies but is replaced by a new muscle cell, it would appear that it is simply a one-for-one tradeoff. Thus, there would be no net increase in the number of muscle cells. Now, imagine what would happen if a muscle cell were stressed enough to elicit the recruitment of satellite cells, but not enough to destroy the insulted myocyte. As you would reason, there would be a net increase in the number of muscle cells. This net increase in the number of muscle cells is referred to as hyperplasia, and it most certainly occurs in birds, in which the majority of satellite cell research has been conducted.
On the other hand, mammalian evidence is more equivocal. The tough question is can a new muscle cell be formed without having killed another? In other words, can satellite cells respond to the mild kind of myocyte damage frequently associated with resistance exercise? This has been area of much debate, but enough evidence exists to make a strong argument that satellite cells can be activated through exercise (16, 23). For example, it has been demonstrated that elite male body builders possess a relatively high incidence of abnormal myofibers, characterized by central as opposed to peripheralnuclei, angular shape, and small diameter. While it is likely that these fibers are the end result of satellite cell activity, it is uncertain if these unusual fibers represent an increase in the total number of muscle cells or have simply replaced those fibers that met an untimely demise (14). It is the conclusion of some, but not all, authors that hyperplasia does certainly occur in mammals (14, 19). If hyperplasia does occur as a result of resistance training in humans, it is unlikely that hyperplasia greatly contributes to overall muscle growth.
Where satellite cells may really work their magic is in the role of supplying extra nuclei to the neighboring muscle cell (14). This occurs by the satellite cells simply migrating into and fusing with the adjacent myocyte and not fusing with one another, as would occur with regeneration (1, 12, 23). The end result is a muscle fiber with more nuclei to instruct the manufacture of muscle proteins. In fact, satellite cells are now considered essential for muscle hypertrophy, at least in some mammals (4, 21). Not surprisingly, the type of exercise may very well be of importance. As it seems that eccentric muscle actions (negatives) are most closely associated with muscle damage, so, too, is satellite cell recruitment most involved with eccentrics (14).
Two different types of satellite cells have been identified: stem satellite cells and committed satellite cells (20). It is this very distinction that may be of paramount importance when it comes to hitting that plateau referred to as one's full genetic potential.
The accepted sequence of events for recruited stem satellite cells goes like this:
1) activation
2) proliferation (mitosis)
3) migration
4) differentiation.
In contrast, committed satellite cells engage in the following:
1) activation
2) migration
3) differentiation
In the latter scenario, there is no proliferation, or cell division; over time, the supply of committed satellite cells could conceivably be exhausted and not replaced. Therefore, as one continues to engage in resistance training, that individual may have fewer and fewer satellite cells to contribute to additional muscle growth. Indeed, from muscle samples taken during surgery, older individuals have exhibited a trend to have less satellite cells than younger folks (3), possibly due to having used up more committed cells over the years.
In addition to training experience, aging also has profound effects on satellite cell response. In addition to a loss in numbers, the satellite cells become stubborn, hard of hearing, and senile in old age. As a person's age increases, satellite cells become less responsive to the many biochemicals previously described and, when activated, require a longer period of time to divide, differentiate, etc. (11, 17) Furthermore, the proliferative potential of satellite cells undergoes a dramatic decline soon after birth, and a more modest but perpetual decline throughout one's life span (17). These facts lend support to the idea that more experienced (i.e., mature) resistance trainees require more time for recuperation and overcompensation (i.e., growth). As a side note, it also supports a notion I've had for a long time that children who are very physically active early in life may exhibit myocytic hyperplasia so that they are more muscular in adulthood, even without exercise. Ever notice that women who were cheerleaders as children and adolescents still possess muscular legs many years after ceasing cheerleading? Hmmm...
As you've read, satellite cells partially determine if your physique can look like it's from out of this world. In the next installment of this series, you'll read about more ultimate regulators of muscle hypertrophy, one of which is guaranteed to shock you with its simplicity!
By Greg Bradley-Popovich, DPT, MSEP, MS, CSCS
© 1999
Originally published in Exercise Protocol
Again we tread on, relentlessly beating back the brushfires of ignorance. This is the second article in a series that attempts to elucidate the mechanisms that play a role in determining "genetic potential" in body building. In other words, we're trying to bring to light that which ultimately limits your muscle growth despite your best and most logical resistance-training efforts.
EP makes every effort to make each article in a series independent so that it can stand on its own without relying on the previous articles. However, because of the complexity of the material presented herein, it may be helpful to review part one in this series.
All too often several accepted and official names exist for the same thing (e.g., "muscle cell" a.k.a "mucle fiber" a.k.a. "myofiber" a.k.a. "myocyte"). In this article, I will utilize all of the aformentioned synonyms. This will be done to annoy you. Seriously, I will use them interchangeably so that readers become familiar and comfortable with all of the terminology, and will not be limited by my personal bias. A goal of EP is to make both your muscles AND your mind grow.
In addition to the genetic material found within a muscle cell, as described in detail in part one, there also exists a virtual reservoir of genetic material residing just outside muscle cells in the form of nuclei within other nearby cells. Because of their peripheral relationship to muscle cells, these reservoirs of genetic material have been aptly named "satellite cells". Luckily, that is their only accepted name, as first given by Alexander Mauro in 1961 (4, 14). Much of our interest in muscle-building potential should probably revolve around satellite cells (pun intended).
(It is worth mentioning that the term "satellite cell" has not been usurped by those cells associated with muscle cells. In fact, the nervous system also possesses cells named satellite cells, though they are not functionally related to those in muscle tissue.)
With an electron microscope, satellite cells appear nestled against myocytes, yet are completely segregated by their own bilayered cell membrane as well as the cell membrane of the muscle cell. Satellite cells may reside in an indentation on the surface of the myocyte, or may be flattened, resulting in a little bump on the surface of the muscle fiber (15). Satellite cells were once simply thought to be spindle-shaped. Now it is recognized that they exhibit a complex morphology (i.e., structure), having many tiny radiating projections (22). Each muscle cell is associated with a few such satellite cells. Satellite cells have a single nucleus that occupies most of the cell's scanty cytoplasm (15). Contrast these little noncontractile cells to mighty myocytes which may have hundreds or even thousands of nuclei (4). The nuclei of satellite cells are simply referred to as "satellite cell nuclei". The nuclei within a muscle cell are called "true myonuclei" (4). All of the nuclei in and surrounding muscle cells (true myonuclei plus satellite cell nuclei) can be referred to generally as "total myonuclei". Some estimates of the total contribution of satellite cell nuclei to total myonuclei in adults vary from as little as 1 percent all the way up to 11 percent (15). However, it is safe to say that the total number of true myonuclei vastly outnumbers the sum of satellite cell nuclei.
Both the satellite cell and the myocyte are enveloped in a continuous connective tissue cobweb. This inner layer of connective tissue that surrounds each and every muscle cell is known as the endomysium (9). Presentation of this information is to facilitate understanding of the structure known as the "basement membrane" or "basal lamina" or "external lamina" (here we go again...), a structure frequently mentioned when discussing satellite cells.
The basement membrane refers to a thin extracellular matrix, which is by definition acellular (i.e., without cells) (9). It lies between the endomysium and the cell membrane of the myocyte (refer to accompanying diagram). The term basement membrane is often incorrectly used interchangeably with the term basal lamina; the basement membrane and the basal lamina are related, but NOT synonymous. Actually, the basement membrane consists of two layers, one of which IS the basal lamina immediately adjacent to the myocytic cell membrane. The other layer of the basement membrane is the reticular lamina, which connects to the endomysium (10). It IS accurate to use the terms basal lamina and external lamina interchangeably when referring to muscle tissue (9, 10). Perhaps surprisingly, it is actually the muscle cell that synthesizes the basal lamina (10), although we may not normally think of muscle cells as having a secretory function. Overall, the role of the basement membrane is to support the adjacent myocyte both structurally and physiologically.
At this point, you may be wondering what, if anything, the basement membrane has to do with the cellular regulation of muscle growth and your genetic potential. Well, if it weren't for the basement membrane, and particularly the basal lamina, satellite cells couldn't fulfill all of their functions. Now onto the meat of the article...
So what is so special about these satellite cells? Actually, without a stressor, satellite cells don't do a hell of a lot. They can ordinarily be considered quiescent, or dormant (4, 14, 15). But we body builders are extraordinary, and that's where satellite cells come into play.
Recall that skeletal muscle cells are postmitotic, meaning they cannot divide to increase in number. This is unfortunate, because if mature skeletal muscle cells could mitotically divide just once, you'd double your muscle mass! Since this is an impossibility, the body does the best it can through satellite cells. The salient quality of satellite cells is that they still possess the ability to divide (5). They are actually leftover muscle precursor cells capable of differentiating into cells referred to as myoblasts (15), a term which literally means "muscle formers".
The phenomenon of satellite cell recruitment is very complex. In addition to a mechanical stressor, the process is apparently influenced by a number of factors and hormones, including hepatocyte growth factor/scatter factor (8, 24), fibroblast growth factor (6), testosterone (12), insulin, insulin-like growth factor I, insulin-like growth factor II (7), and transforming growth factor-beta (1). (A brief explanation of the terms "factor" and "hormone" is warranted: "Often, use of the term 'factor' indicates that the chemical nature of the substance or its mechanism of action are unknown, as in endocrinology where 'factors' are known as 'hormones' when their chemical nature is determined" (25). ) Under the influence of these substances, satellite cell activation and division usually peaks within 1 to 3 days of the initial stressor, at least in small mammals (11, 18, 20).
As we shall see, satellite cells play not just a role in muscle hypertrophy, but also a crucial role in muscle regeneration. Let's begin with regeneration. When a muscle cell is torn, as with a forceful external impact (e.g., getting hit on the deltoid with a baseball) or with a muscle pull or tear, the muscle cell will likely die. In such situations, the basal lamina often persists after a traumatic insult to a muscle cell. So long as the nurturing basal lamina is intact, it serves as a scaffold to guide the regeneration of the muscle cell (10). This process of regeneration occurs by satellite cells immediately around the injured myocyte first mitotically dividing (proliferating), then migrating towards one another (15). The satellite cells are steered during migration to the site of injury by two chemotactic substances secreted by damaged muscle cells: hepatocyte growth factor and transforming growth factor-beta, both mentioned above (2). After migration, the satellite cells, already programmed to form a specific fiber type (13), proceed by differentiating into myoblasts. Then the myoblasts fuse to form what is known as a myotube (15), which eventually manufactures the necessary contractile proteins to become a full-fledged muscle cell. Alternatively, if the basal lamina is also severely disrupted, the muscle cell suffers necrosis (i.e., death), is permanently lost, and is replaced with connective tissue scarring as opposed to another muscle cell derived from satellite cells (10).
How are satellite cells related to muscle growth? Given the above scenario, when a muscle cell dies but is replaced by a new muscle cell, it would appear that it is simply a one-for-one tradeoff. Thus, there would be no net increase in the number of muscle cells. Now, imagine what would happen if a muscle cell were stressed enough to elicit the recruitment of satellite cells, but not enough to destroy the insulted myocyte. As you would reason, there would be a net increase in the number of muscle cells. This net increase in the number of muscle cells is referred to as hyperplasia, and it most certainly occurs in birds, in which the majority of satellite cell research has been conducted.
On the other hand, mammalian evidence is more equivocal. The tough question is can a new muscle cell be formed without having killed another? In other words, can satellite cells respond to the mild kind of myocyte damage frequently associated with resistance exercise? This has been area of much debate, but enough evidence exists to make a strong argument that satellite cells can be activated through exercise (16, 23). For example, it has been demonstrated that elite male body builders possess a relatively high incidence of abnormal myofibers, characterized by central as opposed to peripheralnuclei, angular shape, and small diameter. While it is likely that these fibers are the end result of satellite cell activity, it is uncertain if these unusual fibers represent an increase in the total number of muscle cells or have simply replaced those fibers that met an untimely demise (14). It is the conclusion of some, but not all, authors that hyperplasia does certainly occur in mammals (14, 19). If hyperplasia does occur as a result of resistance training in humans, it is unlikely that hyperplasia greatly contributes to overall muscle growth.
Where satellite cells may really work their magic is in the role of supplying extra nuclei to the neighboring muscle cell (14). This occurs by the satellite cells simply migrating into and fusing with the adjacent myocyte and not fusing with one another, as would occur with regeneration (1, 12, 23). The end result is a muscle fiber with more nuclei to instruct the manufacture of muscle proteins. In fact, satellite cells are now considered essential for muscle hypertrophy, at least in some mammals (4, 21). Not surprisingly, the type of exercise may very well be of importance. As it seems that eccentric muscle actions (negatives) are most closely associated with muscle damage, so, too, is satellite cell recruitment most involved with eccentrics (14).
Two different types of satellite cells have been identified: stem satellite cells and committed satellite cells (20). It is this very distinction that may be of paramount importance when it comes to hitting that plateau referred to as one's full genetic potential.
The accepted sequence of events for recruited stem satellite cells goes like this:
1) activation
2) proliferation (mitosis)
3) migration
4) differentiation.
In contrast, committed satellite cells engage in the following:
1) activation
2) migration
3) differentiation
In the latter scenario, there is no proliferation, or cell division; over time, the supply of committed satellite cells could conceivably be exhausted and not replaced. Therefore, as one continues to engage in resistance training, that individual may have fewer and fewer satellite cells to contribute to additional muscle growth. Indeed, from muscle samples taken during surgery, older individuals have exhibited a trend to have less satellite cells than younger folks (3), possibly due to having used up more committed cells over the years.
In addition to training experience, aging also has profound effects on satellite cell response. In addition to a loss in numbers, the satellite cells become stubborn, hard of hearing, and senile in old age. As a person's age increases, satellite cells become less responsive to the many biochemicals previously described and, when activated, require a longer period of time to divide, differentiate, etc. (11, 17) Furthermore, the proliferative potential of satellite cells undergoes a dramatic decline soon after birth, and a more modest but perpetual decline throughout one's life span (17). These facts lend support to the idea that more experienced (i.e., mature) resistance trainees require more time for recuperation and overcompensation (i.e., growth). As a side note, it also supports a notion I've had for a long time that children who are very physically active early in life may exhibit myocytic hyperplasia so that they are more muscular in adulthood, even without exercise. Ever notice that women who were cheerleaders as children and adolescents still possess muscular legs many years after ceasing cheerleading? Hmmm...
As you've read, satellite cells partially determine if your physique can look like it's from out of this world. In the next installment of this series, you'll read about more ultimate regulators of muscle hypertrophy, one of which is guaranteed to shock you with its simplicity!
