How you can harness the anabolic power of cell volume

Intense training activates protein synthesis - but only if the right nutrients are available to support it.

If you've spent any time thinking about this topic, you'll probably be familiar with the concept of the 'anabolic window' and the importance of nutrition around training.

What happens at a cellular level during the hours after your workout will determine your long-term gains. Use this "anabolic window" to your advantage and you will grow like never before. If you continually miss this window of opportunity, then... well, good luck.

Consuming the right macronutrients at the right times is one of the keys to success, but these macronutrients are only one part of the big picture. An important, yet often overlooked aspect of muscle protein synthesis is cell volume. Increased cell volume isn't just cosmetic, as it makes your muscles look bigger and plumper - it's also one of the key drivers of amino acid transport, working in the background to activate protein synthesis and prevent protein breakdown.

Cell volume: the missing link

A full/volumized muscle is an anabolic muscle. Although we have known for over 20 years that swelling of cells in certain body tissues inhibits protein breakdown and stimulates protein synthesis (1-3), the mechanisms linking cell volume to muscle protein synthesis have been a mystery.

Today we know that protein synthesis is controlled by the enzyme mTOR, which is activated by mechanical stress, growth factors and the amino acid leucine.

While all three of these factors are important for the training stimulus, mTOR signaling is dependent on cell volume (4). This is particularly important in skeletal muscle, where cell volumization activates glycogen synthesis and protein synthesis and inhibits protein degradation (5, 6).

The scientific breakthrough that led to the discovery of the link between cell volume and protein synthesis was achieved in 2005, when a group of scientists discovered that it takes more than just leucine to activate mTOR - glutamine is also needed (7).

This was a surprise. Although glutamine is considered a conditionally essential amino acid that inhibits protein degradation during severe trauma and stress, this amino acid had never before been associated with mTOR activation.

Glutamine is necessary for both leucine uptake and cell volume - both factors required for activation of protein synthesis. The authors of the study were also able to show that cellular depletion of glutamine reserves not only resulted in reduced cell volume, but also reduced the ability of leucine to activate protein synthesis (7).

This was a groundbreaking discovery as it provided a direct link between glutamine, cell volumization and protein synthesis. For the first time, glutamine was shown to be necessary for the activation of protein synthesis by leucine.

Key messages of this study:

• Glutamine is required by leucine to gain access to the cell and activate protein synthesis.
• Glutamine-induced cell volumization is necessary to activate mTOR and protein synthesis.

Although this study suggested that glutamine is a very important piece of the puzzle linking cell volume and protein synthesis, the exact mechanism was not identified until 2009, when Nicklin et al. discovered that glutamine export is coupled to leucine import and mTOR activation (8).

To transport leucine into the cell, an initial phase of "glutamine loading" is required. This also draws water into the cell and thus increases cell volume. After the "glutamine loading phase", glutamine is transported out of the cell in exchange for an import of leucine into the cell.

Nicklin et al. also discovered that cellular glutamine levels are the limiting factor for the activation of protein synthesis by leucine. When cells were simultaneously treated with glutamine and a mixture of EAAs containing leucine, activation of protein synthesis only occurred after a delay of 60 minutes. When the same cells were previously "loaded" with glutamine, protein synthesis was activated within 1 to 2 minutes of leucine administration.

This result was important because it explained the time delay in activation of protein synthesis by leucine in this experimental model.

Key messages of this study:

• Glutamine is the factor that limits the rate of activation of protein synthesis by leucine.
• A cell must first be loaded with glutamine in order to import leucine.

These results ultimately shed light on the cellular machinery that regulates amino acid transport and how this is coupled to the control of protein synthesis.

However, this work must be interpreted with a degree of caution. An important caveat is that these studies were performed in vitro (i.e. with cell cultures), where regulation of protein synthesis is much easier. Muscle cells are capable of producing glutamine on demand from other amino acids and depletion of glutamine reserves in cell cultures is not representative of more physiological situations in vivo.

High rates of protein synthesis cannot be sustained indefinitely in muscle tissue with or without glutamine supplementation. However, glutamine can be used to strategically support protein synthesis by optimizing cell volumization during the post-exercise phase.

Tertiary active transport (TAT): How leucine enters the cell

Cells are very busy and there are many membrane-bound ion channels and transport proteins that regulate "traffic" into and out of the cell. There are two classes of amino acid transporters that are important at this point: "System L" and "System A" amino acid transporters are most closely associated with mTOR signaling and protein synthesis (8-10).

The activity of system L and system A transporters is coupled, which allows leucine and the other BCAAs to be taken up into the cell (11). System L transporters are responsible for the influx of leucine and the other BCAAs in exchange for a flow of glutamine out of the cell.

System A transporters, however, work by a different mechanism in which glutamine is coupled to sodium uptake (12, 13). This coupling of sodium uptake and system L / system A amino acid transporters is referred to as tertiary active transport (TAT for short). It is this TAT that ultimately transports leucine into the cell, leading to activation of mTOR and protein synthesis (11).

You can see how the TAT works in the figure below:

First, a membrane-bound pump called the sodium-potassium ATPase pump (Na+/K+ ATPase, shown in red in the figure above) uses energy from ATP to transport sodium out of the cell against the concentration gradient.

The increased sodium concentration outside the cell is coupled with the import of glutamine into the cell by the system A transporter (shown in yellow in the figure above). The glutamine and sodium influx into the cell also draws water into the cell, resulting in cell swelling. This puts the cell in an anabolic state and prepares the protein synthesis machinery for activation.

When the glutamine concentration within the cell is high enough, the system L transporters (shown in blue in the figure above) are activated, which transport glutamine out of the cell in exchange for an uptake of leucine. The influx of leucine into the cell is the trigger for protein synthesis.

Although this article has been a great lesson in biochemistry so far, the discovery of TAT is not only important for cell biologists. Now that we know how cell volume is linked to amino acid transport and protein synthesis, we can develop some nutritional strategies to maximize this process when it matters most - during the critical post-workout period.

Strategy #1: Maximize your hydration

Protein synthesis is heavily dependent on cellular hydration - even if you are only minimally dehydrated, your ability to recover from intense exercise is severely compromised. Drinking enough water should be a given in this context, but water alone is not enough.

Electrolytes such as sodium, potassium, chloride and phosphate also act as osmolytes as they draw water into the cell. After an intense training session, we need water, amino acids and electrolytes to maximize the cell volumization process that drives protein synthesis.

Sodium, magnesium, calcium, potassium, phosphate and chloride (to name a few) are all important at this point. Up to a certain level, you should not shy away from sodium before or after exercise (unless advised to do so by your doctor). If you lack sodium, your pump from training will be non-existent and sodium is also needed for glutamine uptake.

To eliminate any guesswork, you can turn to electrolyte drinks that contain the ideal ratio of electrolytes to support cell volume and protein synthesis.

Strategy #2: Glutamine loading

Glutamine intake into the cell causes cell volumization and prepares the muscle cell for protein synthesis. As mentioned earlier, a full/volumized muscle is an anabolic muscle. In addition to driving amino acid transport, cell volumization also increases glycogen synthesis and inhibits protein degradation (4-6).

Protein synthesis is suppressed by depletion of glutamine reserves, which has huge implications for hard-training athletes. After an intense training session, an inflammatory response sets in, allowing immune cells to enter damaged muscle tissue and begin the repair/rebuilding process (14).

Glutamine is taken up by immune cells so quickly that it is considered the "energy carrier of the immune system" (15). It is therefore not surprising that intense exercise results in a sharp drop in plasma glutamine levels (16-18).

For this reason, glutamine requirements increase rapidly during the post-exercise phase, as during this time the immune response competes for available glutamine with muscle cells, which require glutamine to prepare for amino acid uptake and protein synthesis.

Premature loading of cells could also potentially reduce the time delay of leucine activation of protein synthesis. If you are not already doing so, you should therefore strongly consider taking 10 to 15 grams of glutamine or glutamine peptides directly after training.

Since BCAAs are preferred substrates for muscle glutamine synthesis and have been shown to increase glutamine production (19-21), BCAAs and leucine are useful during the pre-workout phase to help maximize endogenous glutamine production.

Strategy #3: Prepare the pump

It has recently been discovered that consumption of EAAs increases the expression of system A and system L amino acid transporters (9). Importantly, this occurs at the post-transcriptional level - the level of protein synthesis when existing mRNAs are converted into proteins.

Compared to "de novo" protein expression - where it can take 16 hours or longer to synthesize, process and transport new mRNAs - post-transcriptional activation of protein synthesis can occur within minutes to hours, allowing cells to rapidly increase levels of certain proteins when needed.

Suddenly, we have an even greater incentive to put a solid post-workout nutrition plan into action - EAA supplementation during the pre- and intra-workout phases more than pays off post-workout by increasing the expression of amino acid transporters, priming cells for maximum amino acid uptake and activating protein synthesis.

In addition to isolated EAAs, rapidly absorbable protein isolates and hydrates are ideal during the pre- and intra-workout phase.

Strategy #4: The insulin connection

Insulin is the body's most anabolic hormone. Along with directly activating protein synthesis, insulin also increases the translocation of System A amino acid transporters to the cell membrane (22).

This means that insulin causes more system A transporters to be available at the cell membrane and ready to transport more glutamine into the cell. More glutamine leads to more cell volume, which channels more leucine into the cell and ultimately leads to a higher rate of protein synthesis.

While EAAs increase the expression of amino acid transporters, it is the insulin signal that allows these amino acid transporters to reach the surface of the cell, where they are then ready to transport new amino acids into the cell.

This is another reason why carbohydrates are a good idea before and during exercise unless you are in extreme fat loss mode: Insulin increases the capacity of cellular amino acid transport.

Strategy #5: Insulin potentiating amino acids

Carbohydrates increase insulin levels, but certain amino acids can also be used to increase insulin secretion. Glutamine is a potent activator of incretin hormones, which make insulin-producing cells in the pancreas more sensitive to glucose (23). Glycine also enhances insulin secretion via a different mechanism.

Although carbohydrates alone will increase insulin levels after exercise, by combining these insulin-potentiating amino acids with carbohydrates, you can make your pancreas secrete even more insulin. While it's good to keep insulin levels in the lower range most of the time, elevated insulin levels during the phase around training will maximize amino acid transport, cell volume and protein synthesis while suppressing protein breakdown.

Strategy #6: Buffer lactate production with the help of beta-alanine

The type of intense anaerobic training necessary to build a lot of quality muscle leads to significant lactate production, which lowers the pH in the muscles. Not only does this lead to earlier muscle fatigue and weakness, but certain amino acid transporters, including system A transporters, are inhibited in their activity by a low pH (13).

When the pH within the muscle is low, amino acid uptake is reduced, which inhibits mTOR activation of protein synthesis (24). It has also been shown that inhibition of system A amino acid transporters by low pH increases protein degradation (25).

This is where beta-alanine comes into play. Elevated muscle carnosine levels act as a natural acid buffer and increase the anaerobic stimulus threshold by inhibiting the exercise-induced decrease in muscle pH.

However, beta-alanine also has another important function: it helps to maintain protein synthesis and make it run faster after intensive training by preventing a reduction in amino acid transport.

To increase muscle carnosine levels, you should take 3 grams of beta-alanine daily.

Summary

During intensive training sessions, protein synthesis is reduced and protein breakdown is activated. This is unavoidable for hard-training strength athletes. The degree to which we can minimize the catabolic effects of a hard workout and the faster we can transition back to an anabolic mode after training will ultimately determine how efficiently we recover - and how efficiently we will grow.

The right timing of macronutrients is important, but it is only a means to an end. Cell volume is the driving force for amino acid transport and protein synthesis. If we understand how amino acid transport works and how it is regulated by cell volume, then we can transport more leucine into our training-damaged muscle cells faster, igniting the anabolic fire and ultimately achieving better gains.

The strategies described above are efficient, practical and based on the latest scientific research. Use them to take your training progress to the next level.

By Bill Willis, PhD

Source: https://www.t-nation.com/supplements/how-to-harness-the-anabolic-power-of-cell-volume

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