The Endocrinology of Muscle Growth
The road to anabolic insight must include a biological understanding of what muscle growth actually entails. Often simplified by the term ‘protein synthesis’, muscle growth is actually a highly complex process involving much more than just building proteins from amino acids. Muscle hypertrophy, the correct scientific term for the way we adult humans build skeletal muscle, actually requires the fusion of new cells (called satellite cells) with existing muscle fibers. Since this discovery of satellite cells in 1961, a great deal of research into the mechanisms of muscle hypertrophy has been undertaken. Scientists have come to understand that unlike normal muscle cells, these satellite cells can be regenerated throughout adult life. Furthermore, they serve not as functional units of their own, but provide some of the necessary components to repair and rebuild damaged muscle cells. These satellite cells are normally dormant, and sit resting in small indentations on the outer surface of the muscle fibers, waiting for something to trigger them into activation
Injury or trauma will provide the stimulus necessary to activate satellite cells. Once activated, they will begin to divide, multiply, and form into myoblasts (myoblasts are essentially donor cells that express myogenic genes). This stage of hypertrophy is often referred to as satellite cell proliferation. The myoblasts will then fuse with existing muscle fibers, donating their nuclei. This stage of the process is usually called differentiation. Skeletal muscle cells are multinucleated, which means they possess many nuclei. Increasing the number of nuclei allows the cell to regulate more cytoplasm, which allows more actin and myosin, the two dominant contractile proteins in skeletal muscle, to be produced. This increases the overall cell size and protein content of the muscle cell. Incidentally, the number of nuclei in relation to cross-sectional area also helps to determine the fiber type of the cell, namely slow twitch (aerobic) or fast twitch (anaerobic)332 333. It is important to note that we are not increasing muscle cell number with muscle hypertrophy. We are only increasing cell size and protein content, even though we are using satellite cells to help accomplish this. It is possible for myoblasts to fuse together and actually form new muscle fibers. This is called muscle hyperplasia, and equates to the legitimate growth of new muscle tissue. This is, however, not the primary mechanism of muscle growth in adult life.
The Anabolic Chain
Now that we know what muscle hypertrophy is really about, let’s look at anabolic stimulus and ongoing regulation.
MUSCLE HYPERTROPHY AND THE 4 STAGES OF THE SATELLITE CELL CYCLEDuring the Activation stage, dormant satellite cells are stimulated to enter the cell cycle. Proliferation marks the formation of new myoblasts (active donor cells). These myoblasts will fuse with existing damaged muscle fibers during the Differentiation phase. This allows for greater protein synthesis and the expansion of cell size. Quiescence marks the return to a dormant state, where the inactive satellite cells will again rest on the outer layer of the fibers. Myostatin, a known inhibitor of muscle growth, is believed to be a key regulator in this stage.335 336
The following is a rundown of the chain of hormones and growth factors that mediate muscle growth, from the initiation of damage, to final recovery, repair, and growth. For the sake of organization, I have presented them in what I consider to be three logical phases of action. These are not scientifically accepted definitions. Additionally, we could continue to go deeper and deeper into each of the various compounds, messengers, binding proteins, and receptors involved in this intricate and amazing biological activity. I believe the included text will demonstrate the process of muscle anabolism in a very tangible way, however, without too much unnecessary information. Each of the key areas of this section can be further researched for more detail if you are interested. For one so inclined, the medical references in the endnotes would be an excellent place to start.
We all understand that weight training is fundamental to growing muscle tissue. To date, no “sit on your ass and get huge and ripped’ pill has been invented. The reason is that a number of changes take place in your local muscle tissues during intense training that are vital to the growth process. Without these early changes, growth is difficult if not impossible to stimulate. So for our purposes, we will start here. Training is the ‘trigger’ in the anabolic process. More specifically, it is the localized cellular damage that weight training produces that will first set us down the road of anabolism. The body will respond by repairing this damage, and in the process will try to adapt by making itself stronger. Muscle growth is always a circular process, with a step back (damage) being necessary to take any steps forward.
Phase I: Initial Response
The Initial Response phase covers those changes in muscle chemistry that begin immediately, during training, which will lay the groundwork for later repair and growth. In many regards, the Initial Response Phase will control the potential magnitude of other signals to follow. In the anabolic process, this phase is categorized by the release of arachidonic acid from muscle cells, and the formation of active messengers including prostaglandins, cytokines, leukotrienes, and prostacyclins. This begins with the breakdown of the outer phospholipid layer of muscle cells, which is initiated by the cellular disruption of damaging exercise.334 Phospholipases are released in
response to this trauma, which causes some of the phospholipids stored in the outer layer of the muscle cells to be released. The eccentric part of the exercise movement is of particular importance here, which is the ‘negative” part of the lift, where the muscle is stretched under resistance
The amount of arachidonic acid, which is the central bioactive lipid in the anabolic process, liberated will largely control what occurs during this phase. Arachidonic acid is converted locally and immediately via enzymes to a number of active anabolic end products, the most notable of which in terms of muscle growth) are prostaglandins, which are produced via interaction with cyclooxygenase enzymes. These prostaglandins (PGE2 and PGF2alpha mainly) will control much of the next phase, identified here as the Localized Tissue Priming phase. Additionally, the prostaglandin PGE2 will work to increase local nitric oxide levels, which is also an active molecule in the anabolic process. It has such actions as
dilating blood vessels (to increase the flow of nutrients and hormones to the muscles) and increasing the production of HGF (hepatocyte growth factor) for satellite cell activation. Arachidonic acid contributes to inflammation and pain signaling as well, and its release plays an integral role in the soreness that follows a productive bout of training.
Training intensity and the relative density of arachidonic acid in the phospholipid layer (arachidonic acid availability is ultimately the rate-limiting step in the formation of anabolic prostaglandins) will dictate how much of this potent lipid can be liberated during exercise. The amount of arachidonic acid stored in skeletal muscle tissue is also in a state of constant flux. A number of factors are involved with its regulation, the most notable of which are dietary intake and daily utilization. Regular resistance training depletes arachidonic acid stores, replacing it with other, more abundant, fatty acids.337 With less arachidonic acid available, the responsiveness of the prostaglandin
system to regular exercise starts to diminish.338 Have you ever wondered why you were so sore when you first start training, or after you took a long break? Or why those early workouts tended to be so much more productive than later ones, where you struggle to notice even moderate soreness? Much of this is directly tied to your arachidonic acid stores. The more arachidonic acid you have, the easier it is to liberate during training, and vice versa. Thankfully, levels can be augmented with dietary intervention (for more information, see the arachidonic acid profile).
Phase II: Localized Tissue Priming
Phase II is characterized by a localized increase in growth factor expression and tissue sensitivity to anabolic hormones. Those who have always wondered why anabolic drugs do not work without training will find a good explanation right here. Simply put, your muscles need to be primed for the actions of these drugs first. One way the body accomplishes this is to increase the density of certain receptors in those specific muscles (fibers really) where it needs to initiate repair. This includes, among others, androgen, IGF-1, MGF, and insulin receptors. Stretchinduced muscle damage and the Phase I response are both principle triggers here. Receptor density regulation is important because it prevents anabolic hormones from stimulating tissue growth in areas of the body that do not require it. Receptor density can, therefore, be as strong a regulating force on the pharmacological activity of anabolic drugs as the serum levels of the drugs themselves
To put it in perspective, we need to remember that there are two separate components that interact before any message is sent to a muscle cell telling it to increase growth. We have a hormone or growth factor on one hand, such as testosterone, IGF-1, MGF, or insulin, and its corresponding receptor on the other. Injecting exogenous anabolic drugs facilitates greater receptor binding and anabolic signaling by providing more messenger hormones/growth factors (obviously). The more hormones or growth factors you have around the cell, the more binding and activation of receptor sites will take place. We cannot forget, however, that having more receptor sites (instead of more hormones) can also facilitate the process too. More receptors mean the existing hormones or growth factors will find them faster. Faster binding means the anabolic message is sent more quickly, and once completed that the anabolic messenger will be more likely to find another receptor site (to send another message) before it is broken down by enzymes. It is all about how much signal can be sent in a given time period, and both sides of the equation are equally important in determining this.
While on one hand we have an increase in tissue sensitivity to anabolic hormones and growth factors, also vital during the Localized Tissue Priming phase is an increase in the localized expression of certain vital growth factors themselves. This includes IGF-1, MGF, FGF, HGF, TNF, IL-1, and IL-6. These compounds will be released, and will work together on the existing damaged muscle fibers and satellite cells, in a sort of grand symphony of muscle anabolism, with each playing its own vital role in the
Note: Inhibition of the cyclooxygenase-2 enzyme with anti-inflammatory drugs like ibuprofen, acetaminophen, or aspirin, prevents the formation of active prostaglandins. The anabolic cascade is stalled without sufficient prostaglandin formation (Am J Physiol Endocrinol Metab 282:E551-6), interfering with the normal increase in protein synthesis rates after exercise. It is often advised to use such drugs only when necessary if muscle growth is a key focus.
process. In many cases, the actions of one compound will support the other, either by enhancing its levels, suppressing restricting binding proteins, or supporting its signaling via intertwined mechanisms. A detailed roadmap to all such interactions would go well beyond the scope of this book, and in fact are as of yet not even fully understood to science. A general overview of what is going on with each compound itself, however, is provided in our review of Phase III.
Phase III: Repair
Your local muscle tissues are primed during Phases I and II. During Phase III, the hormones and growth factors go to work to finish the job. We categorize this phase as one of ongoing anabolic action, action mediated by the combined effects of many anabolic hormones and growth factors including androgens, insulin, IGF-1, IGF-2, MGF, FGF, HGF, TNF, IL-1, and IL-6. This is the time when repair and hypertrophy are physically taking place in your muscles, and each compound will play an intricate role in the process. We must not forget, however, that everything leading up to this point (the actions in Phase I & II) has still been determining how strong the growth response will be, via modifying receptor densities and hormone/growth factor expression. We will follow the individual actions of the anabolic components very closely here. During the third phase, tissue repair and growth will be finalized with the help of the following hormones and growth factors.
Hepatocyte Growth Factor (HGF): HGF is a heparin-binding growth factor that resides on the outer surface of uninjured cells. Upon injury, it migrates to satellite cells where it triggers their activation and entry into the cell cycle, 339 HGF expression is regulated via nitric oxide release, 340 which is stimulated upon injury to also aid in the flow of nutrients and hormones to the area. PGE2 plays a pivotal role in nitric oxide synthesis and HGF release.341
Androgens: Androgens (the hormones that anabolic/androgenic steroids mimic) are strong supporters of protein synthesis rates in skeletal muscle tissue. They are also known to stimulate local IGF-1 expression, so the effects of these hormones extend to the satellite cell cycle (perhaps explaining why they are such strong stimulators of muscle growth). It is also of note that arachidonic acid increases androgen receptor density in skeletal muscle tissue. This helps to further piece together the biochemical links between the Phase I and Phase II response.
Insulin-Like Growth Factor 1 (IGF-1): IGF-I is an insulin-like hormone with marked anabolic effects. Owing to its name, it also has some insulin-like effects as well. IGF-1
increases protein synthesis, and supports the proliferation and differentiation of satellite cells. The prostaglandin PGF2alpha is known to strongly up-regulate local IGF-I receptor expression.342 343 PGE2 is also believed to play a role in increasing local IGF-1 synthesis.344
Insulin-Like Growth Factor II (IGF-II): IGF-Il is a second insulin-like growth factor that plays a role in the proliferation of satellite cells. Unlike IGF-I, IGF-Il expression does not appear to drastically increase in response to training.345
Mechano-Growth Factor (MGF): Mechano-Growth Factor is a recently discovered variant of Insulin-Like Growth Factor I. This growth factor is produced during an alternate splicing sequence of the IGF protein, and plays a strong role in the support of myoblast proliferation. MGF expression, like many of the growth factors discussed here, is strongly up-regulated in muscle tissue in response to stretch stimulus.346
Fibroblast Growth Factor (FGF): FGF is actually a family of growth factors, with nine different isoforms (FGF-1 through FGF-9). The full role that FGF plays in muscle hypertrophy in adulthood is not fully understood, however, it is believed to be a strong proliferator of satellite cells, serving to expand their population.347 FGF’s may also play a role in cell differentiation. As with many growth factors, FGF expression up-regulation is proportional to the degree of tissue damage.348 FGF-2 and FGF-4 seem to be the most prolific representatives of this family in mature muscle tissue.
Insulin: In addition to having some ability to increase protein synthesis and inhibit protein breakdown, insulin is the body’s chief nutrient transport hormone. The actions of insulin allow cells to transport glucose and amino acids through the plasma membrane. Insulin receptor expression is strongly up-regulated after traumatic exercise, so as to provide more immediate nutrition to the affected area. This up-regulation has been closely linked to the prostaglandin PGE2.349 350
Cytokines (IL-1, IL-6, TNF): Cytokines are a group of immunomodulatory compounds, though in the context of this section we are loosely referring to them as growth factors. The IL cytokines are called interleukins, and TNF is short for Tumor Necrosis Factor. Among other things, cytokines are known to stimulate the migration of lymphocytes, neutrophils, monocytes, and other healing cells to a site of tissue damage, to aid in cell repair. They help in a number of other ways too, such as aiding in the removal of damaged cells and regulating certain inflammatory responses, including the production of some prostaglandins. Prostaglandins are known to play important roles in the expression of all three of the
cytokines mentioned here,351 352 however, they may not be the sole stimulus. Other pathways of arachidonic acid metabolism may also be involved.
Prostaglandins: Although these are the key initial reactionary chemicals, prostaglandins continue to play a role throughout the muscle building process (including Phase III). This includes their support of hormone receptor proliferation, the enhancement of protein synthesis rates, and an intensification of the anabolic signaling of IGF-1 via a shared pathway (PI3K).353
Estrogens: Although not specifically highlighted in this outline, estrogens also play a minor role in the anabolic process. This includes helping to increase androgen receptor density in certain tissues (though perhaps not skeletal muscle), stimulating the GH/IGF-1 axis, and enhancing glucose utilization for tissue growth and repair.
Bringing it All Together
So that, in a very loose nutshell, is what is going on inside your body from the time you pick up a weight to the time your muscles are repaired, stronger, and ready for more. If the above seems confusing to you, it should. The fact is,
the whole process of muscle growth has been confounding scientists for decades, and undoubtedly will for decades more. We still have a great way to go before being able to explain fully how it is that muscle hypertrophy occurs in humans. But as you can see, we have traveled a great distance as well. During the mid1960s, scientists were only first learning that we grow muscle with the help of satellite cells. More than forty years later we have identified, and are experimenting with, dozens of growth factors that were unheard of back then. It is a new world today, and despite not having all the answers, we know enough to enhance human performance in many exciting new ways. But please don’t mistake the intention of this section. It is not here to give you a functional roadmap of the entire anabolic process, or to guide you in the ultimate polydrug program. It is here simply to open your mind to the true complexity of anabolism. When we start to see muscle growth from its various angles and intricacies, we begin to see our own potential opportunities for successful exploitation. How many of these opportunities you act upon will depend on your own goals and interests. But no matter how much or how little you actually apply this information, I hope you feel better equipped by having it.