November 18, 2012

Everything You Need To Know About Making Every Muscle Cell In Your Body BIGGER!

If you want to build muscle, it’s important to familiarize yourself with the following equations:

1.    Net Muscle Protein Balance (NMPB) = protein synthesis vs. protein breakdown = *hypertrophy

2.    Energy Balance = calories in vs. calories out = weight gain/loss

*Hypertrophy = the increase in muscle fiber size due to an accumulation of contractile and non-contractile proteins inside the cell

The second equation is one that many who’ve sought to lose weight are familiar with. It suggests that if you want to lose weight, than you need to burn more calories than you are taking in. Unfortunately it’s not that simple, as the hormonal response from different foods can prevent you from losing weight, even in a restricted state, but that’s another topic for another time.

The first equation suggests that if you want to build muscle, your body needs to be in a state of a positive NMPB for a greater amount of time than it is either in an equal, or a negative NMPB. The greater positive NMPB, the more muscle will be built. Increasing protein synthesis, decreasing protein breakdown, or a combination of both, increases the likelihood of your body turning the food you eat into muscle! So the million dollar question becomes, ‘how do you maximize protein synthesis, while minimizing protein breakdown’?

The answer to that is multi-faceted, as there are many contributing factors that need to be addressed. The following is by no means a complete list, but is a good start in terms of the most important variables responsible for maximizing protein synthesis:

Satellite cells

Post-workout nutrition

Energy balance


Testosterone (T)

Cortisol (C)

Growth Hormone (GH)





Cell Volume


Each of these factors can be influenced so that you’re putting yourself in the best position to add as much lean muscle to your frame as your body will allow.

The first thing that one needs to understand is the basic physiology of muscle cells, so that they can consciously make the best decisions throughout the day to achieve their muscle building goals.

Before anything else, it is important to point out that the body is between 40-45% muscle, and muscle is between 70-75% water, and 20-25% protein. To quantify those numbers, a 180 lb. male (depending on bodyfat percentage) is roughly 72-81 lbs. of muscle, to which 50.4-60.75 lbs. of it is water, and 14.4-20.25 lbs. of it is protein, thus highlighting the importance of both water and protein if being healthy is important to you, let alone maintaining/building muscle. Without adequate protein and water consumption, you will not build as much muscle as you could if you were ingesting enough protein and water. So if you want to build muscle, you should start there.

Brief rundown of muscle physiology

Muscle cells are multinucleated cells (have more than one nucleus), unlike most body cells which are mononucleated (have only one nucleus). A muscle fiber may have between 250-300 myonuclei per millimetre, indicating that there is a cytoplasm-to-myonucleus ratio. Each myonucleus regulates gene transcription and manages the production of mRNA and protein synthesis for a specific volume within the cell. Hypertrophy beyond 17-25% may put each myonucleus under greater strain, thus increasing the demand for new myonuclei to make continued growth possible. This implies that increases in muscle size must be associated with a proportional increase in myonucleus number, which poses quite the problem since muscle cells are incapable of producing additional myonuclei.

Enter the need for satellite cells

Skeletal muscle contains a population of satellite cells, which have stem cell-like properties enabling them to self-renew, and serve as reserve cells that are recruited when muscular growth (by fusing to existing muscle fibers and donating the nucleus) or regeneration (after injury) is needed. Satellite cells are activated in response to signals associated with muscle damage and mechanical tension, and migrate to the site of injury to repair or replace damaged muscles. If it weren’t for satellite cells donating their nucleus, hypertrophy would be very limited.

The tension provided by strength training stimulates the release of growth factors such as IGF-1 and MGF. IGF-1 is a potent activator of satellite cells, as well as the mTOR (mammalian target of rapamycin) signalling pathway, which is a key regulator in protein synthesis (more on that later).

The effects on NMPB post-workout

The difference between protein synthesis and protein breakdown is termed the Net Muscle Protein Balance (NMPB), as stated above. The processes of synthesis and breakdown of proteins are constant and concurrent, but NMPB will fluctuate throughout the day depending on the exercise and feeding situation. After eating, a rise in anabolic signals will result in rates of protein synthesis exceeding rates of protein breakdown, resulting in a positive NMPB where the muscle will be in a state of anabolism.

On the other hand, during periods of fasting, rates of protein breakdown will exceed rates of protein synthesis, NMPB will become negative and the muscle will be in a catabolic state. Thus, over time, the mass of the musculature will reflect the duration and magnitude of the respective periods of positive and negative NMPB.

After a workout, signalling pathways regulate changes in protein synthesis and breakdown. Protein synthesis is reduced during the initial recovery period after a workout, but there is a marked increase after contraction-related ATP requirements are back to baseline levels. Protein synthesis is doubled between 12-24 hours after the workout, and can remain elevated above baseline values for up to 72 hours, depending on the intensity of the workout (loads above 60% of max are typically needed, and above 80% for more experienced lifters).

Like protein synthesis, protein breakdown is also elevated (25-50% above baseline levels) after working out, especially in those who went a long time without eating (fasted) before the workout. Protein breakdown peaks approximately 3 hours after the workout, before declining, and stays elevated for a far shorter period compared to protein synthesis, returning to baseline levels within 24 hours.

The rate of protein synthesis in the post workout period is greatly influenced on the fed state of the individual, more so than the rate of protein breakdown. Protein synthesis will generally exceed protein breakdown if the individual is fed either before, during, or immediately after exercise, where as breakdown will likely exceed synthesis if the individual is fasted.

As far as dosage, consuming roughly ¼ gram/kg of bodyweight of protein is ideal, and protein synthesis will be doubled compared to fasted, and anything more may not increase protein synthesis further as there is a ceiling effect.

Worth noting is the overall volume of the workout may in fact influence the rate of synthesis compared to rate of breakdown. Theoretically speaking, the more repetitions that are performed during the workout, the greater the protein breakdown that will be.

The importance of energy balance

Protein has always been the focus for increasing muscle mass and strength, but a more important factor is total energy balance. A negative energy balance (in which more calories are burned than are ingested) should be avoided if maximal hypertrophy is the goal. Inducing a state of negative energy balance through dietary restriction and exercise induces a state negative nitrogen balance which is indicative of muscle loss. When energy balance is maintained however, muscle mass may be gained regardless of how many grams of protein is taken per day.

Protein intake may be more important for maintenance of muscle mass during reduced energy intake combined with maintenance of training intensity and volume.

AMPK-mTOR signalling pathways

The major regulator in protein synthesis in response to exercise is the AMPK-mTOR signalling system. mTOR is a gene that regulates the synthesis of proteins, which means that the greater expression of mTOR, the greater level of protein synthesis. Not only does mTOR stimulate many steps that lead to an upregulation of protein synthesis, but also regulates the capacity for protein synthesis by producing more ribosomes, which are the cellular machines that synthesize protein.

mTOR is activated by IGF-1, MGF and phospholipase-D in response to strength training, and also activated by insulin and amino acids, primarily leucine (more on that later).

AMPK has opposite effects of mTOR and reduces protein synthesis and therefore muscle growth. It is however associated with pathways involved in carbohydrate and fatty acid metabolism, which is beneficial for fat loss. AMPK is activated by AMP which increases during exercise, and by low glycogen (glycogen content decreases during exercise).

These distinct genes and signalling pathways that have conflicting actions, and are activated or suppressed in response to endurance and strength related exercise.


Hormones play a role in the muscle building process by regulating protein turnover. Mechanical tension is known to stimulate acute changes in hormone concentrations, which are thought to mediate those cellular processes involved in muscle growth.

Testosterone (T)

T is thought to contribute directly to muscle protein and glycogen synthesis, whilst also reducing muscle protein breakdown, thus having an important anabolic effect upon muscle tissue growth. Indirectly T may also stimulate the release of other anabolic hormones (GH, IGF-1) important for muscle tissue growth.

Hypertrophy protocols (high volume, incomplete rest intervals) typically have the greatest T response, however levels are inversely proportionate to the duration of the workout, meaning that the longer the workout goes on for, the lesser T response.

Cortisol (C)

C is regarded as the primary catabolic hormone as it decreases protein synthesis, and increases protein breakdown. C is a major glucocorticoid and has an important role in metabolism and immune function. The release of C is stimulated by adrenocorticotrophic hormone (ACTH), which is over secreted in response to the increased sensitivity of the hypothalamus-pituitary axis (HPA) to stress. The rise in C occurs roughly 15-30 minutes after ACTH is released.

In metabolism, C causes increases in protein degradation in muscle and connective tissue, amino acid transport into the liver, liver glycogen synthesis, gluconeogenesis (which results in the sparing of blood sugar and protein stores), and lipolysis.

On the flip side, C reduces protein synthesis, amino acid transport to muscle, and glucose uptake and utilization.

As with testosterone, hypertrophy protocols elicit the greatest C response, probably due to the volume (sets X reps) which contributes to overall stress levels on the body. The longer the workout goes on for, the greater C response, which is why many strength and conditioning experts suggest limiting your workouts to no more than one hour.

Testosterone:Cortisol Ratio

Both cortisol and testosterone are made from the same raw material (pregnenolone), so minimizing stress, or anything that could lead to elevated levels of cortisol during parts of the day that don’t require it to be elevated, is in your best interest to create the most anabolic internal environment from a hormonal standpoint.

Growth Hormone (GH)

Unlike steroid hormones (T and C amongst others) GH represents a family of proteins (over 100 molecular isoforms have been identified), rather than a single hormone complex. GH influences muscle growth by increasing protein synthesis by facilitating amino acid transport, and reducing muscle protein breakdown, increasing the metabolism of glucose, as well as by stimulating the release of a family of polypeptides from the liver which are known for their anabolic effects upon muscle tissue (ex. by mediating the production of IGF-1). GH is also lipolytic (stimulates lipolysis), therefore improving body composition!

Like T and C, hypertrophy protocols seem to elicit the greatest GH response.


IGF-1 is a polypeptide hormone with structural similarities to insulin, produced by the liver, and plays a key role in mediating metabolic and anabolic responses during altered energy states. It also has a role in bone and muscle anabolism among many other physiological processes.

MGF, which is one of IGF-1’s isoforms, is preferentially upregulated in response to mechanical signalling and therefore appears to be particularly important to the growth process.

IGF-1 has been shown to induce hypertrophy in both an autocrine, and paracrine [a form of cell signalling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on the same cell (auto), a cell nearby (para), leading to changes in the cell] manner, and exerts its effects directly by increasing the rate of protein synthesis in differentiated myofibers as well as through mediating the proliferation and differentiation of satellite cells.

IGF-1 also mediates the actions of GH – IGF-1 is to GH, what insulin is to carbohydrates.


Insulin is believed to have a strong anabolic effect upon muscle growth, repair and recovery. The actions of insulin mediate the adaptive processors involved in tissue regeneration and growth, whereas other anabolic hormones directly influence cellular reactions and protein accretion, by either binding directly inside the cell (steroid hormones, ex. T and/or C), or on the outside to the cell membrane (peptide hormones, ex. GH).


Roughly 65% of the body’s protein is found within skeletal muscle, and as stated above, muscle is made up of 20-25% protein. The synthesis of new proteins following strength training involves the incorporation of amino acids into proteins primarily involved in muscle contraction (actin and myosin AKA myofibrillar proteins) which make up roughly 80% of all muscle protein.

The synthesis of new proteins occurs when signals within the muscle stimulate the assembly of a specific sequence of amino acids into a chain, which eventually forms the new protein.

BCAA’s are associated with increased muscle protein synthesis and decreased protein breakdown. Leucine, in particular, stimulates the anabolic signalling pathways in the muscle that lead to muscle protein synthesis. Leucine is an insulin secretagogue (a substance that causes another substance to be secreted) and the hyperinsulinemia (a condition in which there are excess levels of circulating insulin in the blood) elicited by leucine ingestion is what attenuates (reduces) rates of protein breakdown.


The acute protein synthetic response is dependent on the type and amount of protein ingested, the timing of protein consumption in relation to the workout, and co-ingestion of other nutrients (ex. carbohydrates), in addition to the type of workout itself.


The influence of carbohydrates on NMPB is likely due to the resulting insulin response. At rest, insulin stimulates anabolic signalling processes and can stimulate increases in protein synthesis provided amino acid availability is maintained. This means, the ingestion of carbohydrates, which elicits increases in plasma insulin, may be beneficial to the anabolic response. Insulin also increases total blood flow, redistributes blood to the muscle bed, and therefore also increases amino acid delivery and uptake into skeletal muscle. However, large increases in muscle protein synthesis occur with amino acid ingestion in the presence of low insulin concentrations. Therefore, carbohydrate ingestion coupled to large elevations in circulating insulin does not appear to be imperative for large increases in muscle protein synthesis.

Moderate increases in insulin increase NMPB in the period after exercise by reducing protein breakdown. An attenuation of muscle protein breakdown will further improve NMPB, leading to muscle protein accretion. Therefore, although the addition of a small/moderate amount of carbohydrate to the ingestion of an amino acid source after exercise may have little effect upon rates of muscle protein synthesis per se, improvements in NMPB may occur through the inhibition of protein breakdown.

Cell Volume

Adequate hydration can result in the cells swelling AKA volumizing, which causes the cell to grow because, as the liquid exerts pressure against the cell wall, it’s perceived as a threat to cellular integrity to which the cell responds by reinforcing its structure (i.e. growth). Cell swelling (intracellular hydration) inhibits protein breakdown, stimulates protein synthesis, as cell volume is the main driver of amino acid transport, also stimulating glycogen synthesis, and activating mTOR, thus creating an anabolic environment by positively affecting NMPB.

The role of glutamine in getting leucine into the cell to turn on protein synthesis

While leucine is required to activate mTOR, all the leucine in the world is of little value if it can’t get into the cell in the first place to activate the gene. So the real question now becomes, ‘how do we get leucine into the cells’?

Glutamine is necessary for cell volumization, priming muscles for glycogen synthesis, while inhibiting protein breakdown, and most importantly, is required for leucine to get into the cell to activate mTOR through the tertiary active transport system. In contrast, glutamine depletion results in a reduction of cell volume, and a reduced ability of leucine to activate protein synthesis.

Membrane-bound ion channels and transport proteins regulate what gets in and out of the cell. It’s the transport proteins that enable leucine to get into the cell and turn on protein synthesis. Here’s how the tertiary active transport system works:

The sodium potassium pump (membrane bound pump) uses ATP to move 2 potassium ions into the cell, and 3 sodium ions out of the cell. The increased concentration of sodium outside the cell activates a specific transport protein that couples sodium with glutamine causing an influx back into the cell, which brings in water as well, causing the cell to swell, putting it into an anabolic state, priming the protein synthesis machinery for activation. When glutamine builds to sufficiently high levels inside the cell a different transport protein is activated, which shuttles glutamine out of the cell in exchange for leucine which is the trigger for protein synthesis.

Other relevant roles of glutamine

Glutamine is considered the fuel of the immune system because it is so rapidly taken up by immune cells, and intense workouts cause glutamine depletion. After a workout, an inflammatory response is mounted, which allows immune cells to traffic into muscle tissue to begin the repair/rebuild process. This is why glutamine requirements are increased after a workout, where the local immune response may be competing for the availability of glutamine to prime muscle cells for amino acid uptake and protein synthesis.


As stated earlier, if you can manipulate each of the above factors in your favour you’re putting yourself in a damn good position to add as much lean muscle to your frame as your body will allow. Here’s a brief summary of how you can do that.

1.    The absolute most important thing you can do is to make sure you ingest more calories each day than you burn, to create a positive energy balance. It’s that simple; if you don’t eat at least as many calories as you burn, you will NOT build more muscle than you already have, even if all your nutrients come from protein.
2.    Because the rate of protein synthesis in the post workout period is greatly influenced on the fed state of the individual, eating frequently to consistently give rise to anabolic signalling, and preventing periods of fasting in which rates of protein breakdown will exceed rates of protein synthesis, is advised.
3.    As far as the AMPK-mTOR signalling pathways are concerned, there are a few choices you are in control of making to ensure that mTOR expression is maximized, and AMPK expression is minimized. Providing your body with amino acid and carbohydrate intake before, during, and after training, blunts AMPK mediated inhibition of mTOR, as well as increasing the expression of the transport proteins involved in getting leucine into the cell, priming the cell for maximum amino acid uptake and activation of protein synthesis. As far as training parameters are concerned, mTOR starts to be inhibited after 60 seconds of continuous tension during a set, and workouts that go beyond one hour (possibly due to glycogen depletion which increases AMP, and therefore activates AMPK, and then inhibits mTOR). Therefore, since full recovery between sets will reduce metabolic demand and enable you to give maximal effort and produce maximal tension every set, full recovery between sets reduces metabolic demand and enable you to give maximal effort and produce maximal tension every set.
4.    Aside from the positive effect on the AMPK and mTOR signalling pathways as it relates to protein synthesis, amino acid and carb consumption also causes more of the transport proteins responsible for getting glutamine into the cell to be displayed on the cell membrane ready to drive more glutamine into the cell, resulting in more cell volume, which drives more leucine into the cell, ultimately leading to more protein synthesis. While protein consumption increases the expression of transport proteins, insulin allows them to be displayed on the cell surface, ready to shuttle new amino acids into the cell. Insulin increases the capacity for cellular amino acid transport.
5.    As for the major anabolic hormones are concerned, hypertrophy protocols seem to be ideal to maximize all of them (T, GH, IGF-1) the most (which is perhaps why bodybuilders display the greatest amounts of hypertrophy out of all strength trained athletes). The duration of the workout however can ultimately influence how much of an anabolic response you will get, as the longer the workout goes on, the greater the cortisol response (along with AMPK becoming increasingly expressed), therefore reducing the anabolic potential.
6.    Aside from AMP being increased as a result of glycogen depleting exercise leading to greater AMPK expression, the transport proteins responsible for getting leucine into the cell are also inhibited by a low pH (which is a result of anaerobic, glycogen depleting strength training), resulting in increased protein breakdown. Low pH also results in reduced amino acid uptake, which suppresses mTOR activation of protein synthesis. Beta-alanine is something that can be taken to increase muscle carnosine levels, and act as a natural acid buffer limiting the decrease in pH from training, as well as preventing the attenuation of amino acid transport after a workout.
7.    And last but certainly not least, as stated earlier, muscles are primarily made up of water (as is the entire body), therefore highlighting the importance of adequate hydration. The more water that you can get into your muscles, the bigger they will get. But just drinking water alone isn’t enough. You need to make sure that you’re getting enough electrolytes like sodium and potassium, as well as glutamine and leucine, so that your cells can “turn on” protein synthesis and begin swelling/building up.

*If your blood pressure and body composition are in the optimal range, then sodium and carbohydrate consumption should only positively affect building muscle as long as everything else is being followed accordingly.

It should go without saying, but common sense isn’t all that common these days, so I’ll reinforce that EVERYTHING suggested in this article is based upon BUILDING MUSCLE! If you are trying to lean out for summer, or a physique type competition, than dramatic changes to the suggestions above ought to be made, so don’t think that by doing everything suggested means you will look like a bodybuilder (or something of the sort). The fact is, bodybuilders (or any physique competitor for that matter) go through dramatic dieting phases in which the goal is NOT to build as much muscle as possible, because they have already done that and now want to make sure it is visible!

Is it really that simple?

The answer to that is yes... and no. If you follow the guidelines presented in this article then building muscle will happen, just as it’s supposed to, at the rate your body will allow. If you are providing your body with the materials it needs to build muscle (protein, carbs, vitamins, minerals, water, etc.), at precisely the most important times (pre, peri, post workout), and are effectively activating mTOR as much, and as frequently as possible while minimizing AMPK, and also generating the most positive anabolic (T, GH, IGF-1, MGF) hormonal response as possible while minimizing catabolic hormones (C), and still can’t build muscle, then you just may be shit outta luck, because those are without a shadow of a doubt, the most influential factors regarding muscle building. Building muscle really is that simple (don’t confuse ‘simple’ with ‘easy’), as most things in life are.

Everybody’s likely heard of the “KISS” principle (Keep It Simple Stupid) at some point in their life. As it relates to building muscle, the bridge that lies between where you’re at now and where you ultimately want to be will be your ability to consistently do what is needed, day in, day out, until you get there. There’s nothing fancy about it, and there’s no real shortcuts. You have to do things right, and you have to do them right all the time. I’ll end it with two quotes;

An excerpt of Vince Lombardi’s speech about winning – “Winning is not a sometimes thing; it’s an all the time thing. You don’t win once in a while; and you don’t do things right once in a while. You do them right all the time”.

As the great Aristotle once said – “We are what we repeatedly do. EXCELLENCE, then, is not an act, but a habit”.

If you have any questions about any of the theories or principles presented in this article, feel free to contact me at I'm available for online consulting and personalized program design, as well as one on one training if you are located in the Greater Toronto Area (GTA).

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