Protein Synthesis Is
Activated By mTOR
Activation of protein
synthesis is controlled by a series of phosphorylation events orchestrated by a
protein called ‘mammalian target of rapamycin’ (mTOR) – which is the
master-controller of protein synthesis in the cell, and thus the most important
cell signaling complex for muscle growth. Muscle growth is directly related to
mTOR activation – greater mTOR activation equals greater protein synthesis,
meaning more new proteins are sent out for muscle growth and repair
mTOR Is Activated 3 Ways
·
Mechanical stress (from training)
·
Growth factors (IGF, growth hormone, insulin, etc.)
·
Amino acids (particularly leucine)
Mechanical tension triggers
protein synthesis, but the response is limited unless the right nutrition is
there to support it, indicating the significance of ‘the anabolic window’ –
pre-/intra-/post-workout nutrition.
To provide your body
with the opportunity to build maximal muscle, you must exploit the anabolic
window because what happens at the cellular level in the hours after training
is predictive of long-term gains.
The 3 Most Important
Times To Consume Amino Acids
The three most
important times for increasing amino acid availability, to facilitate the acute
increase in protein synthesis caused by training are:
·
Pre-workout: Within an hour before training.
·
Intra-workout: During training.
·
Post-workout: Within two hours after training.
Nutrition after the
workout magnifies the acute, exercise induced increase in protein synthesis the
most, but there is still a great deal of value in proper nutrition before, and
during the workout.
Pre-Workout
ATP is burned to
fuel muscle contractions during training, which activates and increases levels
of a protein called AMP kinase (AMPK), which inhibits mTOR and thus blunts the
protein synthetic response. mTOR turns on protein synthesis, AMPK turns it off.
While pre-workout
nutrition doesn't improve the post-workout increase in protein synthesis more
than exercise alone, amino acid intake before training blunts AMPK mediated
inhibition of mTOR, preventing protein synthesis form being turned off during
the workout, setting the stage for a more pronounced effect after the workout.
Intra-Workout
The effect of intra-workout
nutrition is similar to that of pre-workout in that protein intake during a
workout does increase protein synthesis, but not as much compared to when
protein is delivered post-workout, but the main benefit that comes from intra-workout
amino acids is the insulin response which powerfully inhibits protein
degradation.
Including intra-workout
carbs not only inhibit protein degradation, but also blunts AMPK mediated
inhibition of mTOR, keeping protein synthesis turned on during the workout,
further setting the stage for a pronounced effect after the workout.
Post-Workout
Post-workout nutrition
is the most important in regards to upping protein synthesis after a workout
because that’s when muscle cells are primed for protein synthesis.
The type and timing
of protein intake in the post-workout period controls the overall increase in
the protein synthetic response that occurs immediately after a workout, and
this acute response can determine the long term response to training,
which is why training combined with nutrition at precisely the right time is
needed to maximally activate protein synthesis.
The amount of
potential muscle that can be built is limited if protein intake is delayed for more
than two hours after a workout.
The Quality, And
Quantity Of Amino’s Needed
The essential amino
acids (EAAs) are the only ones that activate protein synthesis, with leucine in
particular having the greatest effect, and it's likely that more than 20 grams of
protein is needed to maximize this response.
The Role, And
Importance Of Including Carbs
Insulin is a potent
activator of protein synthesis because it activates mTOR by way of PI3K/akt
signaling, a parallel pathway to that used by amino acids and mechanically
induced stress activation of mTOR, but the purpose of carbs is not to activate
protein synthesis after training since insulin signaling isn't needed to turn
on training-induced protein synthesis.
Because insulin
signaling isn’t needed to spike protein synthesis in the hours following a
workout, the purpose of consuming carbs is because local hyperinsulinemia has a
powerful inhibiting effect on protein degradation.
The Duration Of The
Protein Synthetic Response
Muscles are primed
for increased protein synthesis for over 24 hours after training, but the acute
spike in the protein synthetic response to training or amino acid intake, only
lasts for a few hours, which is why it’s so crucial to optimize nutrition
during this small window. Therefore, each factor contributing the mTOR
activation (mechanical tension, amino acid intake, and insulin/growth factors) must
be maximized since they all activate mTOR through different, but complimentary
pathways, and the more mTOR activating pathways are turned on at the same time,
the more synergistic effect there may be.
Combining All 3
Factors To Maximize Protein Synthesis
Because mechanical tension
and leucine/EAAs synergistically magnify protein synthesis, and insulin
contributes to turning on mTOR through the PI3K/akt pathway, combining insulin
with amino acids can synergistically cause the greatest effect on mTOR
activation.
Even though insulin
doesn't increase exercise-induced protein synthesis, it may act to extend the
duration for the protein synthetic response following training, and extending
or magnifying the protein synthetic response post-workout is reason enough to consume
carbs post-workout, as they can provide a huge muscle building advantage.
Cell Volume Is The
Main Driver Of Amino Acid Transport
While getting the
right macronutrients at the right times is key, another important yet often unknown/misunderstood
aspect of muscle protein synthesis is cell volume, which is the main
driver of amino acid transport.
A Volumized Muscle
Is An Anabolic Muscle
Cell volume is also
linked to protein synthesis, meaning a volumized (full) muscle is an anabolic
muscle, as cell swelling inhibits/suppresses protein degradation/breakdown and
stimulates protein synthesis (in certain cells – skeletal muscle cells being of
greatest importance here).
Protein synthesis is
controlled by the enzyme mTOR, which is not only activated by mechanical stress,
growth factors, and leucine, but mTOR signaling is also dependent on cell
volume. This is especially important in skeletal muscle, where cell
volumization activates protein and glycogen synthesis, and inhibits protein
breakdown.
Glutamine
Glutamine is
considered a ‘conditionally essential’ amino acid, and limits protein breakdown
during severe trauma or stress, but is also linked to mTOR activation because glutamine
is necessary for cell volumization, and to get leucine into the cell, both of
which turn on protein synthesis.
Therefore, cellular
glutamine depletion results in both a reduction of cell volume, and
reduced ability for leucine to activate protein synthesis.
Cell Volume +
Glutamine = Protein Synthesis
There’s a direct
link between, cell volumization, glutamine, and protein synthesis because glutamine
is what enables leucine to get into the cell to activate mTOR, and turn on
protein synthesis, and glutamine induced cell volumization is also turns on
mTOR, and thus protein synthesis.
Cell volume (before,
during, and after training) is critical for getting amino acids inside the
cell, to turn on protein synthesis, and suppress protein breakdown during the
workout.
Glutamine Export Is Coupled
To Leucine Import, And mTOR Activation
Before leucine can
get into the cell, there's an initial period of ‘glutamine loading’, which also
pulls in water, increasing cell volume. After the glutamine is loaded, it is
exported out of the cell in exchange for the import of leucine.
Cellular glutamine
levels are rate limiting for leucine activation of protein synthesis, meaning there
is a lag time (roughly 60 minutes) for the activation of protein synthesis by
leucine when glutamine is consumed simultaneously with an essential amino acid
(EAA) mixture containing leucine, but when cells are ’pre-loaded’ with
glutamine, protein synthesis is turned on almost instantly (within 1-2 minutes)
after leucine is consumed.
Amino Acid Transport
Is Coupled To The Control Of Protein Synthesis
Muscle cells are
capable of making glutamine as needed from other amino acids, but protein
synthesis in muscle tissue can't remain indefinitely elevated, with or without
glutamine supplementation. Glutamine however, can be used to strategically
support protein synthesis by optimizing cell volumization during the
post-workout period.
The Tertiary Active
Transport (TAT) System Is What Gets Leucine Gets Into The Cell
The System ‘A’, and
System ‘L’ transport systems are the two classes of amino acid transporters (transport
proteins regulate what gets in and out of the cell) that are most closely
linked to mTOR signaling and protein synthesis. Their coupled activity is what enables
leucine and the other BCAAs to be absorbed into the cell.
System A
transporters bring glutamine and sodium into the cell, along with water which
causes cell swelling.
System L
transporters bring leucine and the other BCAAs into the cell in exchange for the
glutamine brought in by System A.
The coupling between
sodium uptake and System A / System L amino acid transporters is called Tertiary
Active Transport (TAT), and it's TAT which ultimately drives leucine
inside the cell leading to mTOR activation and protein synthesis.
TAT
First, a membrane
bound pump called the sodium-potassium ATPase pump (Na+/K+ ATPase) uses energy
from ATP to move sodium outside of the cell (against its concentration gradient).
The increased
concentration of sodium outside of the cell is coupled to the import of
glutamine by the System A transporter. The influx of glutamine and sodium, along
with extra water pulled in, causes the cell to swell, putting the cell in an
anabolic state, priming the protein synthetic response.
When glutamine
builds to sufficiently high levels inside the cell, the System L transporters are
activated which shuttles glutamine outside of the cell in exchange for leucine,
and this is what triggers protein synthesis!
Knowing how cell
volume is coupled to amino acid transport and protein synthesis enables several
nutritional strategies to be designed to maximize the process when it counts
most, during the critical post-training period.
The Difference
Between The ‘Pump’, And Cell Volume
A ‘pump’ (reactive
hyperemia) results in increased volume in the areas in-between, and
surrounding muscle cells, also called the ‘interstitial space’, whereas increased
muscle cell volume refers to the actual volume of water inside muscle
cells (and is what drives muscle growth). While the two are not the same, one
(a pump) facilitates the other (increased cell volume).
How The Pump
Facilitates Cell Volume
The vasodilation,
which occurs in response to training, locally increases blood flow to the
working muscles, enhancing the delivery of oxygen and nutrients, as well as
removing waste products. This reaction of increased blood flow (reactive hyperemia
– the pump), results in increased blood plasma in the areas in-between and
surrounding working muscle cells (the interstitial space).
The increased blood
plasma combined with the accumulation of lactate and other metabolites
increases the osmolarity of the interstitial fluid, which creates a
concentration gradient that pulls in additional water from the blood stream,
creating a pump.
The osmotic forces
that conspire to induce the pump actually encourage
cell shrinkage rather than swelling, because if there’s an increase
the concentration of solute on one side of a semi-permeable membrane, water will
diffuse down its concentration gradient until the system reaches equilibrium. In
muscle tissue experiencing a pump, increased osmolarity of the interstitial
fluid encourages water to diffuse out of muscle cells and down its
concentration gradient, which would actually decrease cell volume.
Thanks to a process
known as regulatory volume increase (RVI), muscle cells are able to maintain,
or even increase cell volume, in spite of the increase in extracellular
osmolarity that occurs during a pump which would logically decrease cell volume.
Because of the
coordinated activity of the System A and System L transporter proteins located
in the cell membrane, cell volume increases during a muscle pump.
First, the
sodium-potassium ATPase pump moves three sodium ions out of the cell, in
exchange for two potassium ions. Because the concentration of sodium is
typically 10-20 times higher outside the cells compared to inside, energy is
required in the form of ATP to pump sodium outside the cell, against its concentration
gradient.
Second, another
membrane-associated pump called the sodium-potassium-chloride co-transporter
pump (NKCC), simultaneously transports one sodium, one potassium, and two
chloride ions from outside the cell to inside the cell.
The net result of
these pumps (Na+/K+ ATPase and NKCC) results in a net increase of charged ions
in the cell, which increases intracellular osmolarity. As intracellular
osmolarity increases relative to the interstitial fluid (facilitated by a
muscle pump), extra water is pulled into the muscle, increasing cell volume.
The increased cell
volume generated by the NKCC pump is driven by the sodium gradient created by
the Na+/K+ ATPase pump.
As stated above, the
extracellular sodium gradient created by the sodium-potassium ATPase pump not
only increases cell volume, it also drives amino acid uptake inside the cell, turning
on protein synthesis and repairing damaged muscle. Once again, while all of the
essential amino acids activate protein synthesis to a certain extent, leucine
is the most potent trigger, which is transported through this TAT mechanism.
Summary
Training turns on
protein synthesis and protein degradation, and the amount of new size and
strength there is to gain is based on the ability to consistently shift the
balance toward protein synthesis and away from protein breakdown after every
single workout. Because protein turnover increases substantially in the minutes
to hours after training, maximizing cell volume with optimal workout nutrition
is critical to long-term progress.
To kick-start the
muscle growth/repair process after training, we need to get leucine inside the
cell, which is driven by cell volume, dependent on the sodium gradient induced
by the sodium-potassium ATPase pump.
At the most basic
level, both increased cell volume and amino acid uptake are dependent on
sodium, potassium, ATP, and water.
Practical
Application
Properly Timed
Workout Nutrition
By this point it’s
obvious that nutrient timing around the workout period can make or break your
ability to recover and improve.
Amino acids are osmolytes
that pull in additional water when transported into cells increasing cell
volume.
Insulin activates
amino acid transport, and also increases cell volume by inducing glucose
uptake. While macronutrient timing is important, there are additional
considerations to be made in order to maximize intra-workout cell volume
potential:
Pre-Workout (~45
minutes before)
Functional carbs
such as highly-branched cyclic dextrin will keep insulin levels steady along
with fast-acting protein hydrolysates.
To maximize cell
volume, sodium, water, and to a lesser extent, potassium, magnesium, and
calcium are all important here as well.
The sodium-potassium
ATPase pump creates the extracellular sodium gradient that makes cell
volumization, amino acid uptake, and even glucose uptake possible. Although you
should be properly hydrated well in-advance of the workout, water intake should
be further increased during this time.
Protein: 30-50g of any
medium to fast-acting protein source (ex. mixtures of whey and casein
isolates/hydrolysates and concentrates). Whole-food protein is okay an hour
before training, no less than a half hour before though (an hour being ideal).
Carbs: 25-75g of low to
medium GI carbs (ex. a cup of oatmeal with a cup of blueberries). Carbs are optional,
but should be included if you plan to train hard.
Pre-Workout (15
minutes before) and intra-workout
Functional carbs and
fast-acting protein hydrolysates in liquid-form.
During this period,
as well as during the actual workout, water and electrolyte intake (sodium,
potassium, magnesium, and calcium) are crucial to promote maximal nutrient
uptake and cell volume.
A product specifically
designed for this purpose can take the guesswork out of it, one that contains
functional carbs, and quick-acting peptides from casein hydrolysate, and
is loaded with all the electrolytes required in the correct ratios to
promote maximal increases in cell volume.
Creatine use is
ideal here, because creatine uptake efficiency may increase in response to the
increased interstitial osmolarity that causes a muscle pump during training.
Protein: 10-20g of BCAA or
20-30g of isolates/hydrolysates from casein, or whey
Carbs: 35-50g of high GI
carbs, drank throughout the workout. Carbs are optional, but the insulin
response from carbs may synergistically amplify protein synthesis in the presence
of amino acids, while also a powerfully inhibiting protein degradation.
There's a
fat-burning advantage to keeping insulin low for those who are pre-contest or
are insulin resistant, in which case it may be best to omit carbs here,
however, the insulin response can be very helpful for those strictly looking to
put on size.
Post-workout (within
60 minutes after)
Protein hydrolysates
to promote continued protein synthesis, and from a cell volume standpoint
continued water and electrolytes consumption, followed by rest.
EAA intake during
the pre-and intra-workout periods pays off bigtime in the post-workout period
by increasing the expression of amino acid transporters (System A and System L –
which happens at the ‘post-transcriptional level’, where existing mRNA’s are
translated into proteins), priming the cell for maximum amino acid uptake and activation
of protein synthesis, allowing cells to rapidly increase the level of particular
proteins when needed.
This is why fast-absorbing
protein isolates or hydrolysates during the pre-and intra-workout periods are
ideal.
Protein: 30-50g fast-acting
protein, whey isolates/hydrolysates, or casein hydrolysate
Carbs: 25-75g of
medium-to low GI carbs, depending on the individual, their goals, and phase of
training. Off-season lifters or hard-gainers can get away with 50-100g of a
mixture of medium to high GI carbs. Carbs are optional, but highly advised unless
drastic fat reduction is needed.
True hard-gainers
can really benefit from the protein degradation inhibiting effects of insulin
here. The big spike in insulin from the high GI carbs and more sustained
elevation from medium GI carbs may sustain the protein synthetic response
longer.
It’ ok to
occasionally omit carbs altogether here for those who are pre-contest or insulin
resistant people, but don't make it a habit.
Hydration
Optimal cell volume,
activation of protein synthesis, and inhibition of protein breakdown are all
dependent on proper hydration. Even slight dehydration can impair performance,
and compromise the ability to recover from intense training.
Optimize
Electrolytes – Water Alone Isn't Enough
Maintaining optimal
levels of osmotically active molecules (electrolytes, which function as osmolytes)
such as sodium, potassium, magnesium, and to a lesser extent chloride, calcium,
phosphorous, are needed to draw water into the cell and increase cell volume.
Potassium, and
especially sodium, in particular are required for cell volumization and amino
acid uptake (since sodium is necessary for glutamine uptake), both before and
after the workout, because blood volume is highly dependent on sodium levels, meaning
the ability to get, and sustain a pump while training, will be almost
non-existent if you're sodium-depleted.
Regularly consuming
potassium-rich foods is ideal as well – potatoes, broccoli, bananas, squash, are
all excellent potassium sources.
Function of the
Na+/K+ ATPase and NKCC pumps are also dependent on magnesium, meaning a
deficiency will compromise cell volumization.
Water, amino acids,
and electrolytes are all needed post-workout to maximize the cell volumization process
that drives protein synthesis.
Creatine Monohydrate
– The Original Cell Volumizer
Creatine is an
important osmolyte which supports cell volumization both directly, and
indirectly. Creatine is stored in muscle cells as phospho-creatine which directly
increases cell volume by pulling additional water into the cell when it's
absorbed, and also supplies a high-energy phosphate group to regenerate ATP
during high intensity contractions, and provide the sodium-potassium ATPase
pump with the energy needed (in the form of ATP) to move sodium outside the
cell against its concentration gradient which facilitates cell volume
indirectly. This function is so important for life itself that upwards of 30%
of total cellular ATP is used just to keep the sodium-potassium ATPase pump
running.
5 grams a day is all
that is needed.
Glutamine Loading
Glutamine increases
glycogen synthesis and inhibits protein breakdown, and glutamine uptake into
the cell causes cell volumization, which primes muscle cells for protein
synthesis because a full/volumized muscle is an anabolic muscle.
Protein synthesis is
limited by glutamine depletion. After an intense training session, an
inflammatory response is mounted, which allows immune cells to traffic into
thrashed muscle tissue to begin the repair/rebuilding process.
Glutamine is rapidly
taken up by immune cells, which is why it's considered the ‘fuel of the immune
system’, and is also why plasma glutamine is depleted following intensive
training.
Since glutamine
requirements are elevated in the post-workout period, and the local immune
response may be competing for the availability of glutamine to prime muscle
cells for amino acid uptake and protein synthesis, pre-loading cells with
glutamine may reduce the ‘lag-time’ associated with leucine-activation of
protein synthesis.
10-15g of glutamine
or glutamine peptides immediately post-workout, along with BCAA’s since they
increase muscle glutamine production (BCAAs and leucine are also useful
during the pre-workout period to help maximize endogenous glutamine production),
is all that is needed.
The Insulin
Connection
Along with directly
activating protein synthesis, insulin also increases translocation of the
System A amino acid transporters to the cell membrane, meaning that insulin
causes more System A transporters to be displayed on the cell membrane, ready
to drive more glutamine into the cell, which leads to more cell volume, which
drives more leucine into the cell, and ultimately contributes to greater
protein synthesis.
While EAAs increase
the expression of amino acid transporters, it's the insulin signal
that allows them to be displayed on the cell surface, ready to shuttle new
amino acids into the cell.
This is yet another
reason why pre-and intra-workout carbs are a good idea unless you're in extreme
fat loss mode, as insulin increases the capacity for cellular amino acid
transport.
Insulin–Potentiating
Amino Acids
Certain amino acids
(ex. glutamine) can be used to potentiate insulin release. Glutamine is a
powerful activator of ‘incretin’ hormones, which make insulin-producing cells
in the pancreas more sensitive to glucose. Glycine is another that potentiates
insulin release, but through a different mechanism.
Although
post-workout carbs alone will increase insulin levels, combining these insulin-potentiating
amino acids with carbs will supercharge the pancreas for a greater insulin
release. While it's best to keep insulin levels on the lower side most of the
time, increased insulin levels in the intra-workout period maximizes amino acid
transport, cell volume, and protein synthesis, while also suppressing protein
breakdown.
Beta-Alanine To Buffer
Lactate Production
The type of training
geared towards building muscle produces considerable amounts of lactate, which lowers
muscle pH, results in early muscle fatigue and weakness, reduced amino acid
uptake (which suppresses mTOR activation of protein synthesis), and inhibits certain
amino acid transporters, including System A, increasing protein breakdown.
Beta-alanine increases
muscle carnosine levels and acts as a natural acid buffer, extending anaerobic
threshold by limiting the reduction in muscle pH from training, and also helps
maintain, and kick-start protein synthesis after intense training by preventing
the attenuation of amino acid transport.
Maximize Mechanical
Tension To Create A Highly Anabolic State
While cell
volumization is a fundamental driver of muscle growth and recovery, the
volumized muscle still needs to be placed under a great deal of mechanical
tension because part of the mechanism by which cell swelling activates protein
synthesis is through increased tension on the cytoskeleton which directly
increases protein synthesis by enhancing mRNA translational efficiency. High-intensity
muscle contractions directly activates/increases amino acid uptake and protein
synthesis, in part by activating the sodium-potassium ATPase pump.
Nutrient Wrap-Up
Nutrients have a
potent effect on the protein synthetic response, and timing them right can make
or break your training progress.
During intense
training sessions, protein synthesis is reduced and protein degradation is
activated. The extent to which we can minimize the catabolic effects of
training and the quicker we can return to ‘anabolic mode’ during the post-
training period ultimately determines how efficiently we'll recover and grow.
Macronutrient timing
is important, but it is a means to an end. Cell volume is the main driver
of amino acid transport and protein synthesis. By understanding how amino
acid transport happens and how it's regulated by cell volume we can get more
leucine into trashed muscle cells faster, thereby stoking the anabolic fire and
ultimately leading to better gains.
If you have any
questions about any of the strategies presented in this article, feel free to
contact me at ben@paramounttraining.ca. 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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