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Two of the most frequently thrown around words in bodybuilding subculture are “anabolic” and “catabolic”. However, I’m guessing that the majority of laypeople don’t actually know much about these terms beyond the fact that the former refers to building and the latter to breaking down.
Given that the main focus of many physique competitors and athletes alike is to improve their body composition, muscular hypertrophy and fat loss are often their primary concerns. Therefore, it seems prudent to cover the basics of what exactly anabolism and catabolism mean in these respects. Moreover, it’s important to understand what these two classes of reactions mean in the grand scheme of things for living organisms.
This guide is intended to cover the major factors of the human endocrine system and their role in protein anabolism and catabolism. Carbohydrate and fatty acid metabolism will be covered in a separate guide, along with the role of anaerobic & aerobic exercise and blood flow.
All living organisms are made up of the simplest living unit—the cell. Yes, this means even simple microbial organisms are “alive”, granted humans are composed of an enormous number (think 100s of trillions) of cells and are highly encephalized while many microbes exist as a single cell (and don’t have brains). But I digress…
Back to the concern at hand, within these cells, chemical reactions are constantly occurring while utilizing and giving off energy in the process. These reactions are divided into two classes that we alluded to in the introduction, those being anabolic and catabolic; the former uses energy to build cell components and molecules while the latter gives off energy as they break down complex substrates.
Therefore, when we speak of metabolism, we are referring to the summation of all of these physiological reactions within the cell that are necessary to sustain life. A multitude of variables such as hormone signaling, physical activity, nutrient availability, and energy status affect how these reactions occur and when they take place. For now, just know that metabolism is a highly intricate system of reactions in cells that sustain life, and there is an inherent energy input & output from these processes (thus the need for nutrients).
However, these events are theoretically mutually exclusive as one scenario requires an energetic deficit and the other requires an energetic surplus. Thus, when I come across a trainer or some magic program that “guarantees” it will help you build muscle and lose fat at the same time, I know to steer clear as that is a pretty arrogant claim unless that individual plans to overcome thermodynamic laws.
So one way to think of improving body composition is like a see-saw between building muscle and losing fat—if you want to increase one then the other will have to decrease.
This is why the traditional approach for many gym-goers looking to improve their body composition is to alternate between periods of building muscle mass and losing fat; colloquially, people usually refer to these timeframes as “bulking” and “cutting”, respectively. The other option is to be in a “maintaining” phase (neither building/losing muscle nor losing/gaining fat).
Related: How Protein Consumption & Quality Impact Body Composition
So let’s take a look at what role protein anabolism and catabolism play when it comes to this predicament of improving one’s body composition.
However, many people misconstrue the message being sent when someone refers to protein synthesis. Proteins are essential macromolecules that play a myriad of roles in humans; they are not solely relegated to muscle tissue and in fact, are quite ubiquitous throughout many body systems:
Here is a preview of the topics to be covered:
When the body is in a state of starvation (and other catabolic instances), amino acids are released from muscle tissue into circulation and utilized by other body tissues. On the contrary, when protein anabolism is necessary, amino acids can be actively transported from circulation into the intracellular space of muscle cells and incorporated into proteins (thus synthesizing new protein).
So in addition to the availability of intracellular amino acids, protein synthesis/anabolism is also regulated in part by the transport of amino acids into and out of muscle cells.
In animals (mainly carnivores) amino acids provide a generous amount of energy from the oxidation of amino acids. The oxidation of amino acids to ammonia and their subsequent carbon skeletons occurs when there is excessive protein in the diet or during states of starvation, carbohydrate restriction, and/or diabetes mellitus.
Ammonia is excreted as urea via the kidneys in humans, while the carbon skeletons of amino acids enter the citric acid cycle for the production of energy. Some people claim that the stress placed on the kidneys from high protein intake is a case against traditional “bodybuilding diets”, but even upwards of 2 grams of protein per pound of lean bodyweight appear to be safe for those with healthy renal function (though that is a rather exorbitant intake for most natural trainees).
However, I can assure you that if your goal is to build a lean, muscular physique, then you’ll be well served to let insulin work its anabolic mojo rather than trying to avoid it all costs like so many anti-carb advocates suggest.
Related: Carbs Aren't Making You Fat - The Truth About Insulin
Insulin is one of the most potent anabolic hormones in the human body and acts to induce protein anabolism in the entire body when amino acids are replenished. The key here is that a state of hyperinsulinemia (elevated insulin levels) without concomitant availability of amino acids doesn’t appear to increase whole-body protein synthesis (though it does reduce the rate of whole-body protein breakdown).1, 2, 3
Moreover, while insulin does reduce whole-body protein breakdown, it does not modulate the ubiquitin system that is responsible for the regulation of muscle protein breakdown. Therefore, insulin is not a specific reducer of muscle protein breakdown.4
Research suggests that insulin doesn’t directly alter the rate of transmembrane transport of (most) amino acids but it rather increases muscle protein synthesis by drawing on the active intracellular pool of amino acids.5 The exceptions to this are amino acids that use sodium-potassium pumps (mainly alanine, leucine, and lysine) as insulin causes skeletal muscle cells to be hyperpolarized by activation of those pumps.2
This suggests that a state of hyperinsulinemia paralleled with a state of hyperaminoacidemia (elevated plasma amino acid levels) should be quite conducive to facilitating muscle protein synthesis. This is in fact why patients in a state of critical cachexia are often set up with an infusion of amino acids and insulin.
As noted above, a state of hyperinsulinemia and hyperaminoacidemia will facilitate muscle protein synthesis, and what better way to induce such a state than by simply ingesting protein and carbohydrates.
However, be careful not to misconstrue the message here to mean “the more insulin the better” as this doesn’t appear to be the case in physiological ranges. Research seems to indicate that while some insulin does amplify the muscle protein synthesis response to feeding, there is a point of saturation in which extra insulin doesn’t confer a more intense response.6
Many people believe that a superfluous rush of fast-acting carbohydrates along with whey protein is ideal, especially after weight training to maximize the muscle protein synthetic response. The reality is you don’t have to “spike” your insulin; a slow, transient insulin response (as seen with low glycemic load carbohydrates) will provide much the same muscle protein synthesis benefits as a rapid, acute surge.
For practicality purposes, it is important to consider the actions of IGFBP-3 since nearly all IGF-1 is bound to one of 6 protein complexes and IGFBP-3 makes up about 80% of all this binding.
It is suggested that IGF-1 has effects similar to insulin (at high concentrations) on protein metabolism due to its ability to bind and activate the insulin receptor, albeit at a much less potent rate (about 1/10th the potency of insulin).7
Therefore, it’s not surprising that IGF-1 administration promotes protein anabolism in skeletal muscle and the whole body.8, 9 A unique characteristic of IGFBP-3 is that it appears to inhibit skeletal muscle atrophy (i.e. it’s anti-catabolic).10
Well, several factors influence the amount of IGF-1/IGFBP-3 (and GH) present in the blood at any given moment, including, but not limited to: genetics, biorhythms, age, exercise, nutrient status, stress, disease state, and ethnicity.
However, many people may assume that an increase in insulin will confer a subsequent elevation in IGF-1, which is not the case (remember, insulin and IGF-1 are structurally and somewhat mechanistically similar, but they’re produced in different fashions). Intuitively, since GH is ultimately what leads to the production of IGF-1 (roughly 6-8 hours post GH release/administration), it makes the most sense to focus on elevating endogenous GH levels (which we will discuss in the growth hormone section of this guide).
Editor's Note on Deer Antler Velvet supplements that claim to increase IGF-1: In recent years some supplement companies have tried to make the claim that deer antler velvet extracts are conducive to skeletal muscle growth and healing in humans due to the potent amount of IGF-1 contained in said extracts. However, don’t fall prey to the hype behind these supplements as IGF-1 is a peptide hormone, therefore any oral form of it will be rapidly cleaved in the gastrointestinal (GI) tract before it gets into circulation. This is why people who are type-1 diabetics have to inject insulin (also a peptide hormone) and can’t just take an oral form of it since that too would be degraded by the GI tract.
GH seems to be one of the most misunderstood hormones in the body with some so-called “fitness gurus” claiming it isn’t anabolic at all or even beneficial from a health standpoint (which is quite an arrogant thing to say given the body of scientific evidence against such claims). GH does indeed have a variety of anabolic actions in the human body, but they are mechanistically different from those of insulin. GH may be viewed as the primary anabolic hormone during stress and fasting, whereas insulin is the major anabolic hormone in the preprandial timeframe.
Research has shown that GH strongly inhibits amino acid oxidation (recall from earlier that amino acids may be oxidized for energy). Thus, GH acts to spare crucial amino acids in the amino acid pools, resulting in greater availability of those amino acids for incorporation into proteins.11
That being said, it appears that GH is a promoter of whole-body protein synthesis in the short-term and any increases in muscle protein synthesis from GH administration are likely the result of downstream paracrine (local) IGF-1 release. Both GH and testosterone (which we will cover later in this guide) increase paracrine IGF-1 which could be of benefit for anabolic effects in skeletal muscle tissue.
A curious finding is that in studies that give subjects exogenous doses of IGF-1, the expression of paracrine IGF-1 is suppressed, and thus no increase in muscle protein synthesis is observed.7, 12, 13 Therefore, the use of IGF-1 as a performance-enhancing drug does not seem very pragmatic, at least for someone looking to acquire more skeletal muscle tissue.
It has been shown that GH not only promotes protein synthesis but also inhibits protein degradation, and it is likely that this effect is seen in skeletal muscle tissue due to paracrine expression IGF-1.14 The reason for attributing these anabolic effects to GH is quite simply because GH subsequently creates IGF-1.
A final point to consider with regards to the anabolic actions of GH is that it accelerates the transport of several essential amino acids across the cell membrane, specifically those mediated by System L—the major transport system responsible for sodium-independent transport of neutral amino acids (such as leucine, isoleucine, and valine).15
To recap, GH is a potent hormone that promotes whole-body protein synthesis and decreases whole-body protein breakdown, and it is likely that those effects could be induced in skeletal muscle tissue as well once the downstream production of paracrine IGF-1 kicks in (hopefully more research will be directed towards this concern in the coming years).
GH also strongly inhibits the oxidation and increases the transmembrane transport, of important amino acids such as the branched-chain amino acids leucine, isoleucine, and valine. Also of note is that GH is a major influencer on fat loss since it promotes the use of free fatty acids for energy.
As was noted in the above IGF-1 section, a variety of factors play into when and how much GH is secreted. Given that GH is secreted in a pulsatile fashion (with about 50% of the total daily secretion occurring during deep sleep) it is worthwhile to consider the following list of GH secretion stimulators and inhibitors:
Stimulators of GH secretion:16-22
There are several androgens produced in the adrenal glands of humans, but the main one we will focus on here is testosterone (mainly produced in the testes of males and ovaries of females) given that it is the primary male sex hormone and most potent natural/endogenously-produced anabolic steroid.
There is a significant body of evidence that shows testosterone plays a pivotal role in the growth and maintenance of skeletal muscle tissue. In studies administering hypogonadal men a replacement dose of testosterone, fat-free mass, skeletal muscle strength, and muscle protein synthesis all increase rather dramatically.27, 28, 29 This effect has also been replicated in trained athletes and normal, healthy men upon administration of pharmacological doses of various androgens.30, 31
It appears that mechanistically testosterone, similarly to GH, exerts part of its anabolic effects by decreasing amino acid oxidation (specifically leucine) and increasing their uptake into whole-body and skeletal muscle proteins.32
Furthermore, there appears to be a synergistic (but independent) anabolic effect between testosterone and GH, enhancing their benefits on skeletal muscle protein synthesis.33
Like GH and IGF-1, many factors play into modulating endogenous production of testosterone; below is a truncated list of some of these variables.
Positive effectors: 35, 36, 37, 38, 39, 40
In females, most estrogens are produced in the ovaries via aromatization of androstenedione, while in males it is produced in small amounts in the testes and more so from aromatization of testosterone in fat cells.
Unlike all the hormones we’ve discussed up to this point, estrogens appear to have both anabolic and catabolic properties with regards to protein metabolism (mainly through the mediation of other hormones in the body).
Studies have shown that estrogens increase systemic GH levels and paracrine IGF-1, both of those being favorable characteristics for protein anabolism and anti-catabolism. [44, 45, 46] Moreover, estrogens promote water retention which is conducive to cell volumization and thus anabolism.
However, when excess estrogen is present it can be indirectly catabolic by blockading androgen receptors and down-regulating the production of gonadotropin-releasing hormone in the hypothalamus ultimately lowering the production of testosterone in the body.
Just be cautious as excess estrogen levels (especially in males) will likely decrease testosterone production and availability, thereby impeding the positive effects of testosterone on protein metabolism.
Some general health tips to balance your estrogen production include:47-50
Research seems to suggest that thyroid hormones increase both whole-body protein synthesis and degradation, but more so the latter than the former, resulting in a net catabolic effect on whole-body protein metabolism.51, 52
In general, thyroid hormones in normal physiological ranges play a basic role in regulating protein metabolism, and it’s improper to extrapolate the data from hyperthyroidism (synthetically induced in the studies) protocols to mean that a euthyroid state is inherently catabolic. That being said, there doesn’t appear to be any benefits to skeletal muscle or whole-body protein anabolism by increasing thyroid production or using exogenous thyroid to achieve a hyperthyroid state, and if anything, it will likely have a net catabolic effect.
However, if your goal is anabolism (especially of skeletal muscle tissue) it doesn’t seem wise to manipulate your thyroid levels. This is to say that the best way to go for proper protein metabolism would be to simply maintain a euthyroid state/be within the normal physiological range.
Glucocorticoids are a class of steroid hormones produced in the adrenal glands that regulate metabolism, development, immune function, and cognition/alertness. The primary glucocorticoid produced in humans is the stress hormone cortisol. Cortisol is an essential hormone necessary to sustain life, but like with many other hormones, too much (or too little) of it can wreak havoc on the body.
Cortisol is often implicated in the process of muscle atrophy/loss since it mainly acts as a catabolic hormone with regard to its metabolic functions. During periods of undernourishment/fasting, cortisol acts to maintain nominal glucose concentrations in the blood by initiating gluconeogenesis. Often times this comes at the cost of degrading proteins in order to utilize amino acids as a substrate for the gluconeogenic process.
Glucagon is a peptide hormone produced in the pancreas that functions basically in reverse to insulin (e.g. it stimulates the release of glucose from the liver into the bloodstream when blood sugar drops). Similar to cortisol, glucagon influences gluconeogenesis and also glycogenolysis.
The final hormone in this triad is epinephrine/adrenaline (sometimes referred to as the “fight-or-flight” hormone). This hormone is produced in the central nervous system and adrenal glands and acts on pretty much all tissues in the body by binding adrenergic receptors. As with cortisol and glucagon, epinephrine stimulates glycogenolysis in the liver (and muscle).
Protein synthesis rates in skeletal muscle tissue appear to decrease somewhat dramatically in response to stress hormone infusions.53, 54, 55 It appears that during prolonged exposure to stress hormones muscle protein synthesis is impaired, leading to atrophy of muscle tissue.56
Also of note is that epinephrine and cortisol may inhibit insulin secretion, and recall from earlier that insulin is an anabolic hormone. Some research also suggests that cortisol blunts the synthesis of paracrine IGF-1, which as aforementioned would be counterproductive to the goal of protein anabolism.57
The data does seem to show that infusions of these hormones promote protein breakdown in most tissues throughout the body and stimulates the oxidation of amino acids. They may also impair protein synthesis after chronic exposure and blunt the release of insulin and paracrine IGF-1. Ultimately the summation of these actions results in a net catabolic effect.
However, don’t misconstrue this message to mean that acute bursts of these hormones (as seen during times of acute stress) are counterproductive to muscle growth since that is missing the bigger picture; again, stress hormones are a necessary part of human physiology. Unless you have abnormally high cortisol, glucagon, and epinephrine concentrations in the blood for prolonged periods of time (e.g. Cushing’s Syndrome, chronic stress, etc.) there probably isn’t much reason to fret over lowering or inhibiting these hormones as is just not practical or healthy.
This guide is not intended to promote the use of any of the compounds/hormones discussed herein without the supervision/permission of a trained physician. The options laid out in this guide to modulate the levels of some of these hormones are all meant to act via endogenous production, not exogenous administration.
Lastly, remember that many physiological processes are not black-and-white functions or on/off switches. It is always imperative that we take into account circumstances and the context of the situation at hand. It is impractical, and ill-advised, to discount individual variables that come into play when offering someone advice with regards to their diet, nutrition, and training.
Therefore, this guide is meant to serve as a broad overview of the factors that mediate protein metabolism and give you, the reader, the necessary information to devise the optimal eating and lifestyle habits to achieve your physique and performance goals.
Given that the main focus of many physique competitors and athletes alike is to improve their body composition, muscular hypertrophy and fat loss are often their primary concerns. Therefore, it seems prudent to cover the basics of what exactly anabolism and catabolism mean in these respects. Moreover, it’s important to understand what these two classes of reactions mean in the grand scheme of things for living organisms.
This guide is intended to cover the major factors of the human endocrine system and their role in protein anabolism and catabolism. Carbohydrate and fatty acid metabolism will be covered in a separate guide, along with the role of anaerobic & aerobic exercise and blood flow.
1. What is Metabolism?
Metabolism is one of those terms that pretty much everyone knows (and uses) but yet few actually understand, so this section will serve to give you an elementary grasp of what exactly metabolism is.All living organisms are made up of the simplest living unit—the cell. Yes, this means even simple microbial organisms are “alive”, granted humans are composed of an enormous number (think 100s of trillions) of cells and are highly encephalized while many microbes exist as a single cell (and don’t have brains). But I digress…
Back to the concern at hand, within these cells, chemical reactions are constantly occurring while utilizing and giving off energy in the process. These reactions are divided into two classes that we alluded to in the introduction, those being anabolic and catabolic; the former uses energy to build cell components and molecules while the latter gives off energy as they break down complex substrates.
Therefore, when we speak of metabolism, we are referring to the summation of all of these physiological reactions within the cell that are necessary to sustain life. A multitude of variables such as hormone signaling, physical activity, nutrient availability, and energy status affect how these reactions occur and when they take place. For now, just know that metabolism is a highly intricate system of reactions in cells that sustain life, and there is an inherent energy input & output from these processes (thus the need for nutrients).
2. Improving Body Composition
The goal of almost any individual in the gym is to improve their body composition (i.e. reduce body-fat levels and/or increase muscle mass). The conundrum is that improving body composition is a give-and-take process. In bodybuilding and the fitness subculture, many people become obsessed with the idea of simultaneously losing fat and building muscle.However, these events are theoretically mutually exclusive as one scenario requires an energetic deficit and the other requires an energetic surplus. Thus, when I come across a trainer or some magic program that “guarantees” it will help you build muscle and lose fat at the same time, I know to steer clear as that is a pretty arrogant claim unless that individual plans to overcome thermodynamic laws.
So one way to think of improving body composition is like a see-saw between building muscle and losing fat—if you want to increase one then the other will have to decrease.
This is why the traditional approach for many gym-goers looking to improve their body composition is to alternate between periods of building muscle mass and losing fat; colloquially, people usually refer to these timeframes as “bulking” and “cutting”, respectively. The other option is to be in a “maintaining” phase (neither building/losing muscle nor losing/gaining fat).
Related: How Protein Consumption & Quality Impact Body Composition
So let’s take a look at what role protein anabolism and catabolism play when it comes to this predicament of improving one’s body composition.
3. Protein and Building Skeletal Muscle Tissue
Skeletal muscle tissue serves as the largest reservoir of amino acids in the human body. Many bodybuilders and health enthusiasts love discussing the topic of protein intake, mainly because proteins provide the “building blocks”/amino acids necessary to synthesize muscle tissue.However, many people misconstrue the message being sent when someone refers to protein synthesis. Proteins are essential macromolecules that play a myriad of roles in humans; they are not solely relegated to muscle tissue and in fact, are quite ubiquitous throughout many body systems:
- Whole-body protein turnover - this is a measurement of the synthesis and breakdown of protein in all organs, skeletal and non-skeletal
- Skeletal muscle protein turnover - this is a measurement of the synthesis and breakdown throughout skeletal muscle tissue
4. Important Terminology
Before moving on, hopefully, those of you who get a bit confused with all the technical jargon will benefit from this quick overview of some terms that will be used throughout this guide:- Muscle protein synthesis - refers to the synthesis of protein in skeletal muscle tissue only
- Muscle protein degradation - refers to breakdown/degradation of skeletal muscle tissue only
- Protein turnover - a measurement that detects that balance between protein synthesis and protein degradation
- Muscle protein anabolism - refers to a state in skeletal muscle tissue where synthesis exceeds degradation, and thus lean tissue is being built.
- Muscle protein catabolism - refers to a state in skeletal muscle tissue where degradation exceeds synthesis, and thus lean tissue is being broken down
- Hypertrophy - the growth of tissue (generally in reference to muscle)
- Atrophy - tissue shrinkage; opposite of hypertrophy
5. Factors That Affect Muscle Protein Anabolism and Catabolism
Okay, so now we have arrived at the meat and potatoes of this guide and will get into what factors play a large role in protein anabolism and catabolism, which ultimately have ramifications on body composition. As alluded to earlier, anabolic reactions serve to build cellular components and molecules while catabolic reactions do the opposite. Also, recall that anabolic reactions require energy input and catabolic reactions give off energy. So we will breakdown how protein anabolic and catabolic reactions play a role with regards to building skeletal muscle tissue—one of the most pertinent components to improving body composition.Here is a preview of the topics to be covered:
- Amino acid pooling, transport, and oxidation
- Insulin
- Insulin-like Growth Factor-1 (IGF-1) and IGF-Binding Protein-3 (IGFBP-3)
- Growth hormone
- Androgenic hormones
- Estrogenic hormones
- Thyroid hormones
- “Stress hormones” - glucocorticoids, glucagon, and catecholamines
5a. Amino Acid Pooling, Transport, and Oxidation
As noted earlier, skeletal muscle tissue serves as the largest reservoir of amino acids in the body and makes up the largest mass of protein. There are essentially two amino acid pools we are concerned with here–the circulating pool and intracellular pool.When the body is in a state of starvation (and other catabolic instances), amino acids are released from muscle tissue into circulation and utilized by other body tissues. On the contrary, when protein anabolism is necessary, amino acids can be actively transported from circulation into the intracellular space of muscle cells and incorporated into proteins (thus synthesizing new protein).
So in addition to the availability of intracellular amino acids, protein synthesis/anabolism is also regulated in part by the transport of amino acids into and out of muscle cells.
In animals (mainly carnivores) amino acids provide a generous amount of energy from the oxidation of amino acids. The oxidation of amino acids to ammonia and their subsequent carbon skeletons occurs when there is excessive protein in the diet or during states of starvation, carbohydrate restriction, and/or diabetes mellitus.
Ammonia is excreted as urea via the kidneys in humans, while the carbon skeletons of amino acids enter the citric acid cycle for the production of energy. Some people claim that the stress placed on the kidneys from high protein intake is a case against traditional “bodybuilding diets”, but even upwards of 2 grams of protein per pound of lean bodyweight appear to be safe for those with healthy renal function (though that is a rather exorbitant intake for most natural trainees).
5b. Insulin
Insulin is a peptide hormone secreted in the pancreas of humans mainly in response to elevations in blood sugar levels (since it acts as an up-regulator of glucose transport proteins). With the onset of a dramatic increase in type-2 diabetes in the United States, insulin has unfortunately found itself being cast down as the enemy of human physiology as we know it.However, I can assure you that if your goal is to build a lean, muscular physique, then you’ll be well served to let insulin work its anabolic mojo rather than trying to avoid it all costs like so many anti-carb advocates suggest.
Related: Carbs Aren't Making You Fat - The Truth About Insulin
Insulin is one of the most potent anabolic hormones in the human body and acts to induce protein anabolism in the entire body when amino acids are replenished. The key here is that a state of hyperinsulinemia (elevated insulin levels) without concomitant availability of amino acids doesn’t appear to increase whole-body protein synthesis (though it does reduce the rate of whole-body protein breakdown).1, 2, 3
Moreover, while insulin does reduce whole-body protein breakdown, it does not modulate the ubiquitin system that is responsible for the regulation of muscle protein breakdown. Therefore, insulin is not a specific reducer of muscle protein breakdown.4
Research suggests that insulin doesn’t directly alter the rate of transmembrane transport of (most) amino acids but it rather increases muscle protein synthesis by drawing on the active intracellular pool of amino acids.5 The exceptions to this are amino acids that use sodium-potassium pumps (mainly alanine, leucine, and lysine) as insulin causes skeletal muscle cells to be hyperpolarized by activation of those pumps.2
This suggests that a state of hyperinsulinemia paralleled with a state of hyperaminoacidemia (elevated plasma amino acid levels) should be quite conducive to facilitating muscle protein synthesis. This is in fact why patients in a state of critical cachexia are often set up with an infusion of amino acids and insulin.
Insulin Summary:
All the scientific mumbo jumbo can sometimes cause us to lose sight of the bigger picture. The take-home message is that insulin is indeed a highly anabolic hormone that is conducive to skeletal muscle protein synthesis but that an exogenous source of amino acids is necessary to create this effect.As noted above, a state of hyperinsulinemia and hyperaminoacidemia will facilitate muscle protein synthesis, and what better way to induce such a state than by simply ingesting protein and carbohydrates.
However, be careful not to misconstrue the message here to mean “the more insulin the better” as this doesn’t appear to be the case in physiological ranges. Research seems to indicate that while some insulin does amplify the muscle protein synthesis response to feeding, there is a point of saturation in which extra insulin doesn’t confer a more intense response.6
Many people believe that a superfluous rush of fast-acting carbohydrates along with whey protein is ideal, especially after weight training to maximize the muscle protein synthetic response. The reality is you don’t have to “spike” your insulin; a slow, transient insulin response (as seen with low glycemic load carbohydrates) will provide much the same muscle protein synthesis benefits as a rapid, acute surge.
5c. Insulin-like Growth Factor-1 (IGF-1) & IGF-Binding Protein-3 (IGFBP-3)
As you may have likely derived from the nomenclature, IGF-1 is a peptide hormone quite similar in molecular structure to insulin and has implications on the growth of humans. IGF-1 is produced mainly in the liver upon binding of growth hormone (GH) and acts either locally on select tissues (paracrine) or systemically (endocrine); thus, IGF-1 is a mediator of the effects of GH. IGF-1 is a potent initiator of the AKT signaling pathway in cells, which has ramifications on cell growth and proliferation.For practicality purposes, it is important to consider the actions of IGFBP-3 since nearly all IGF-1 is bound to one of 6 protein complexes and IGFBP-3 makes up about 80% of all this binding.
It is suggested that IGF-1 has effects similar to insulin (at high concentrations) on protein metabolism due to its ability to bind and activate the insulin receptor, albeit at a much less potent rate (about 1/10th the potency of insulin).7
Therefore, it’s not surprising that IGF-1 administration promotes protein anabolism in skeletal muscle and the whole body.8, 9 A unique characteristic of IGFBP-3 is that it appears to inhibit skeletal muscle atrophy (i.e. it’s anti-catabolic).10
IGF-1/IGFBP-3 Summary:
Given that IGF-1/IGFBP-3 is beneficial with respect to stimulating protein anabolism and preserving skeletal muscle tissue in times of muscle wasting/cachexia, the most prudent question most people are probably wondering about is, “How do we increase circulating levels of these moieties?”Well, several factors influence the amount of IGF-1/IGFBP-3 (and GH) present in the blood at any given moment, including, but not limited to: genetics, biorhythms, age, exercise, nutrient status, stress, disease state, and ethnicity.
However, many people may assume that an increase in insulin will confer a subsequent elevation in IGF-1, which is not the case (remember, insulin and IGF-1 are structurally and somewhat mechanistically similar, but they’re produced in different fashions). Intuitively, since GH is ultimately what leads to the production of IGF-1 (roughly 6-8 hours post GH release/administration), it makes the most sense to focus on elevating endogenous GH levels (which we will discuss in the growth hormone section of this guide).
Editor's Note on Deer Antler Velvet supplements that claim to increase IGF-1: In recent years some supplement companies have tried to make the claim that deer antler velvet extracts are conducive to skeletal muscle growth and healing in humans due to the potent amount of IGF-1 contained in said extracts. However, don’t fall prey to the hype behind these supplements as IGF-1 is a peptide hormone, therefore any oral form of it will be rapidly cleaved in the gastrointestinal (GI) tract before it gets into circulation. This is why people who are type-1 diabetics have to inject insulin (also a peptide hormone) and can’t just take an oral form of it since that too would be degraded by the GI tract.
5d. Growth Hormone (GH)
GH is a peptide hormone produced in the pituitary gland that stimulates cellular growth and reproduction. When subjects are well-nourished, GH stimulates the production of insulin from the pancreas and IGF-1 once it reaches the liver which subsequently promotes the growth of lean body mass, adipose tissue, and storage of glucose. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of free fatty acids for use as energy, thus preserving lean body mass and glycogen stores.11GH seems to be one of the most misunderstood hormones in the body with some so-called “fitness gurus” claiming it isn’t anabolic at all or even beneficial from a health standpoint (which is quite an arrogant thing to say given the body of scientific evidence against such claims). GH does indeed have a variety of anabolic actions in the human body, but they are mechanistically different from those of insulin. GH may be viewed as the primary anabolic hormone during stress and fasting, whereas insulin is the major anabolic hormone in the preprandial timeframe.
Research has shown that GH strongly inhibits amino acid oxidation (recall from earlier that amino acids may be oxidized for energy). Thus, GH acts to spare crucial amino acids in the amino acid pools, resulting in greater availability of those amino acids for incorporation into proteins.11
That being said, it appears that GH is a promoter of whole-body protein synthesis in the short-term and any increases in muscle protein synthesis from GH administration are likely the result of downstream paracrine (local) IGF-1 release. Both GH and testosterone (which we will cover later in this guide) increase paracrine IGF-1 which could be of benefit for anabolic effects in skeletal muscle tissue.
A curious finding is that in studies that give subjects exogenous doses of IGF-1, the expression of paracrine IGF-1 is suppressed, and thus no increase in muscle protein synthesis is observed.7, 12, 13 Therefore, the use of IGF-1 as a performance-enhancing drug does not seem very pragmatic, at least for someone looking to acquire more skeletal muscle tissue.
It has been shown that GH not only promotes protein synthesis but also inhibits protein degradation, and it is likely that this effect is seen in skeletal muscle tissue due to paracrine expression IGF-1.14 The reason for attributing these anabolic effects to GH is quite simply because GH subsequently creates IGF-1.
A final point to consider with regards to the anabolic actions of GH is that it accelerates the transport of several essential amino acids across the cell membrane, specifically those mediated by System L—the major transport system responsible for sodium-independent transport of neutral amino acids (such as leucine, isoleucine, and valine).15
Growth Hormone Summary:
GH is a highly complex hormone that’s under much investigation as many of its in vivo actions are yet to be elucidated.To recap, GH is a potent hormone that promotes whole-body protein synthesis and decreases whole-body protein breakdown, and it is likely that those effects could be induced in skeletal muscle tissue as well once the downstream production of paracrine IGF-1 kicks in (hopefully more research will be directed towards this concern in the coming years).
GH also strongly inhibits the oxidation and increases the transmembrane transport, of important amino acids such as the branched-chain amino acids leucine, isoleucine, and valine. Also of note is that GH is a major influencer on fat loss since it promotes the use of free fatty acids for energy.
As was noted in the above IGF-1 section, a variety of factors play into when and how much GH is secreted. Given that GH is secreted in a pulsatile fashion (with about 50% of the total daily secretion occurring during deep sleep) it is worthwhile to consider the following list of GH secretion stimulators and inhibitors:
Stimulators of GH secretion:16-22
- Sex hormones (androgens and estrogen)
- Peptide hormones such as ghrelin and growth hormone-releasing hormone (GHRH)
- L-DOPA, the precursor to the neurotransmitter Dopamine
- Nicotinic acid (Vitamin B3)
- Nicotinic receptor agonists
- Somatostatin inhibitors
- Fasting
- Deep sleep
- Intense exercise
- Somatostatin
- Hyperglycemia (e.g. carbohydrates in the bloodstream)
- IGF-1 and GH (due to negative feedback inhibition on the pituitary gland)
- Xenobiotics
- Glucocorticoids
- Certain sex hormone metabolites, such as dihydrotestosterone (DHT)
5e. Androgens
Many readers are likely familiar with the term anabolic androgenic steroid (AAS) that is often used in the media and fitness subculture. That right there tells you that androgens are indeed anabolic hormones, and they influence the development and maintenance of male sex organs and secondary sex characteristics.There are several androgens produced in the adrenal glands of humans, but the main one we will focus on here is testosterone (mainly produced in the testes of males and ovaries of females) given that it is the primary male sex hormone and most potent natural/endogenously-produced anabolic steroid.
There is a significant body of evidence that shows testosterone plays a pivotal role in the growth and maintenance of skeletal muscle tissue. In studies administering hypogonadal men a replacement dose of testosterone, fat-free mass, skeletal muscle strength, and muscle protein synthesis all increase rather dramatically.27, 28, 29 This effect has also been replicated in trained athletes and normal, healthy men upon administration of pharmacological doses of various androgens.30, 31
It appears that mechanistically testosterone, similarly to GH, exerts part of its anabolic effects by decreasing amino acid oxidation (specifically leucine) and increasing their uptake into whole-body and skeletal muscle proteins.32
Furthermore, there appears to be a synergistic (but independent) anabolic effect between testosterone and GH, enhancing their benefits on skeletal muscle protein synthesis.33
Androgens Summary:
There are many reasons testosterone (and other androgens) are so heavily researched, and it’s quite clear that these compounds have a myriad of anabolic actions in the human body. Testosterone is a strong inhibitor of amino acid oxidation and increases whole-body and skeletal muscle protein synthesis (and also appears to have anti-proteolytic effects).34Like GH and IGF-1, many factors play into modulating endogenous production of testosterone; below is a truncated list of some of these variables.
Positive effectors: 35, 36, 37, 38, 39, 40
- Adequate sleep
- Fat loss (to a degree, since fat cells secrete aromatase)
- Vigorous exercise (especially resistance training)
- D-Aspartic Acid supplementation
- Vitamin D supplementation
- Abstinence (for roughly one week at a time)
- Obesity/Over-fatness
- Lack of sleep
- Diabetes (specifically insulin-resistant/type II diabetes)
- Sedentary lifestyle/inactivity
- Very-low fat diets
- Prolonged aerobic/cardiovascular exercise
- Excessive alcohol intake
- Xenobiotics
5f. Estrogenic Hormones
Estrogens are quite plainly the principal female sex hormones and responsible for the growth and maturation of female reproductive tissues, but they are still present in males (albeit at much lower concentrations). There are three major estrogens produced in the steroidogenesis pathway of humans: estradiol, estrone, and estriol. Estradiol, on a molar basis, is about 10 times more potent than estrone and 80 times more potent than estriol with respect to its estrogenic effects.In females, most estrogens are produced in the ovaries via aromatization of androstenedione, while in males it is produced in small amounts in the testes and more so from aromatization of testosterone in fat cells.
Unlike all the hormones we’ve discussed up to this point, estrogens appear to have both anabolic and catabolic properties with regards to protein metabolism (mainly through the mediation of other hormones in the body).
Studies have shown that estrogens increase systemic GH levels and paracrine IGF-1, both of those being favorable characteristics for protein anabolism and anti-catabolism. [44, 45, 46] Moreover, estrogens promote water retention which is conducive to cell volumization and thus anabolism.
However, when excess estrogen is present it can be indirectly catabolic by blockading androgen receptors and down-regulating the production of gonadotropin-releasing hormone in the hypothalamus ultimately lowering the production of testosterone in the body.
Estrogen Summary:
Like with many other things in the health and fitness world, there is a balance to be found when it comes to your estrogen levels. Estrogens have a medley of important effects in the human body and even a few anabolic/anti-catabolic effects on protein metabolism.Just be cautious as excess estrogen levels (especially in males) will likely decrease testosterone production and availability, thereby impeding the positive effects of testosterone on protein metabolism.
Some general health tips to balance your estrogen production include:47-50
- Eating a well-balanced diet that has ample vitamins/minerals and adequate dietary fiber.
- Limiting the intake of soy and phytoestrogens from plant products
- Limiting alcohol intake as alcohol impairs the liver’s ability to metabolize estrogens
- Maintaining a regular workout/exercise regimen
- Maintain a healthy body weight, avoiding obesity or being severely underweight
5g. Thyroid Hormones
Thyroid hormones are a major regulator of metabolic rate and affect nearly every cell in the human body. The thyroid gland produces thyroxine (T4) and triiodothyronine (T3), with T4 being the prohormone of T3. On a molar basis, T3 is about 20 times as potent as T4 and is thus considered the “true” thyroid hormone (most T3 in circulation comes from the deiodination of T4).Research seems to suggest that thyroid hormones increase both whole-body protein synthesis and degradation, but more so the latter than the former, resulting in a net catabolic effect on whole-body protein metabolism.51, 52
In general, thyroid hormones in normal physiological ranges play a basic role in regulating protein metabolism, and it’s improper to extrapolate the data from hyperthyroidism (synthetically induced in the studies) protocols to mean that a euthyroid state is inherently catabolic. That being said, there doesn’t appear to be any benefits to skeletal muscle or whole-body protein anabolism by increasing thyroid production or using exogenous thyroid to achieve a hyperthyroid state, and if anything, it will likely have a net catabolic effect.
Thyroid Summary:
Being that the main goal of this guide is to discuss the ramifications of these hormones/factors on protein metabolism specifically, the above section doesn’t discuss the role that thyroid hormones play in fat and carbohydrate metabolism. Just know that the catabolic nature of thyroid hormones means they would be favorable for fat loss due to the up-regulation of metabolic rate (thus many people who have hyperthyroidism are usually underweight and/or have a hard time gaining weight).However, if your goal is anabolism (especially of skeletal muscle tissue) it doesn’t seem wise to manipulate your thyroid levels. This is to say that the best way to go for proper protein metabolism would be to simply maintain a euthyroid state/be within the normal physiological range.
5h. Stress Hormones
The term “stress hormones” is often used in research literature to refer to glucocorticoids (mainly cortisol), glucagon, and catecholamines (specifically epinephrine/adrenaline). This is primarily due to the fact that their secretion is stimulated, quite plainly, in response to stress (note that stress isn’t always a “bad” thing, which would be more properly termed distress).Glucocorticoids are a class of steroid hormones produced in the adrenal glands that regulate metabolism, development, immune function, and cognition/alertness. The primary glucocorticoid produced in humans is the stress hormone cortisol. Cortisol is an essential hormone necessary to sustain life, but like with many other hormones, too much (or too little) of it can wreak havoc on the body.
Cortisol is often implicated in the process of muscle atrophy/loss since it mainly acts as a catabolic hormone with regard to its metabolic functions. During periods of undernourishment/fasting, cortisol acts to maintain nominal glucose concentrations in the blood by initiating gluconeogenesis. Often times this comes at the cost of degrading proteins in order to utilize amino acids as a substrate for the gluconeogenic process.
Glucagon is a peptide hormone produced in the pancreas that functions basically in reverse to insulin (e.g. it stimulates the release of glucose from the liver into the bloodstream when blood sugar drops). Similar to cortisol, glucagon influences gluconeogenesis and also glycogenolysis.
The final hormone in this triad is epinephrine/adrenaline (sometimes referred to as the “fight-or-flight” hormone). This hormone is produced in the central nervous system and adrenal glands and acts on pretty much all tissues in the body by binding adrenergic receptors. As with cortisol and glucagon, epinephrine stimulates glycogenolysis in the liver (and muscle).
Protein synthesis rates in skeletal muscle tissue appear to decrease somewhat dramatically in response to stress hormone infusions.53, 54, 55 It appears that during prolonged exposure to stress hormones muscle protein synthesis is impaired, leading to atrophy of muscle tissue.56
Also of note is that epinephrine and cortisol may inhibit insulin secretion, and recall from earlier that insulin is an anabolic hormone. Some research also suggests that cortisol blunts the synthesis of paracrine IGF-1, which as aforementioned would be counterproductive to the goal of protein anabolism.57
Stress Hormones Summary:
The take-home message here is not that these stress hormones are not some “evil” hormones that should be avoided/inhibited at all costs because frankly, that’s just not what you want (in fact they’re essential to life in many ways).The data does seem to show that infusions of these hormones promote protein breakdown in most tissues throughout the body and stimulates the oxidation of amino acids. They may also impair protein synthesis after chronic exposure and blunt the release of insulin and paracrine IGF-1. Ultimately the summation of these actions results in a net catabolic effect.
However, don’t misconstrue this message to mean that acute bursts of these hormones (as seen during times of acute stress) are counterproductive to muscle growth since that is missing the bigger picture; again, stress hormones are a necessary part of human physiology. Unless you have abnormally high cortisol, glucagon, and epinephrine concentrations in the blood for prolonged periods of time (e.g. Cushing’s Syndrome, chronic stress, etc.) there probably isn’t much reason to fret over lowering or inhibiting these hormones as is just not practical or healthy.
6. Bringing It All Together
While this guide is fairly rife with scientific jargon, I hope it serves readers with an understandable overview of some major factors that affect protein metabolism. This is a complex topic and protein metabolism is a growing field of research, but that’s what makes it worthwhile to investigate and discuss.This guide is not intended to promote the use of any of the compounds/hormones discussed herein without the supervision/permission of a trained physician. The options laid out in this guide to modulate the levels of some of these hormones are all meant to act via endogenous production, not exogenous administration.
Lastly, remember that many physiological processes are not black-and-white functions or on/off switches. It is always imperative that we take into account circumstances and the context of the situation at hand. It is impractical, and ill-advised, to discount individual variables that come into play when offering someone advice with regards to their diet, nutrition, and training.
Therefore, this guide is meant to serve as a broad overview of the factors that mediate protein metabolism and give you, the reader, the necessary information to devise the optimal eating and lifestyle habits to achieve your physique and performance goals.
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