Boosting Cell Volume For Growth
by Bill Willis, PhD T-Nation
Here's what you need to know...
• Cell volume is critical for getting amino acids inside the cell. It's also the fundamental property of substances like creatine.
• Cell volume and the pump, while related, aren't the same thing. Cell volume refers to fluid within the muscle cells, while the pump has to do with fluid in-between muscle cells.
• Even though the cell volume and the pump are different, a great pump can facilitate increased cell volume and lead to greater growth.
Nothing is more satisfying after a workout than a skin-splitting pump. It lets you know you've done a good job after an all-out training session. The working muscle is so "full" that even slight movement is a challenge, and you can literally feel the blood coursing through your arteries.
The fact that our muscles tend to feel extra full during periods of increased growth, even in-between workouts, isn't a coincidence. A full muscle is an anabolic muscle, and increased muscle cell volume works behind the scenes as a driver for anabolic muscle growth.
It's generally assumed that the best way to increase cell volume is to get great pumps in the gym. Cell volume and the pump, while related, aren't the same thing, however. Whereas cell volume refers to the actual volume of water inside muscle cells, a pump, or reactive hyperemia, in physiological terms, refers to increased volume in the areas in-between and surrounding muscle cells, also called the "interstitial area."
In spite of this distinction, getting a great pump can, under the right circumstances, facilitate increased cell volume. If you haven't considered this variable as part of your overall workout nutrition strategy, you should. Cell volume is critical for getting amino acids inside the cell, turning on protein synthesis, and suppressing protein breakdown during the critical peri-workout window: before, during, and after training.
The Anatomy of a Muscle Pump
In response to high-intensity exercise, vasodilation locally increases blood flow to hard working muscles, enhancing the delivery of oxygen and nutrients as well as removing waste products. This reactive hyperemia, also known as the pump, results in increased blood plasma in the areas in-between and surrounding working muscle cells (the interstitial space).
The combination of increased blood plasma and accumulation of lactate and other metabolites increases the osmolarity of the interstitial fluid (1). This creates a concentration gradient that pulls in additional water from the blood stream(2, 3), creating the phenomenon that we all know so well as "the pump."
Since the pump is generally considered to be synonymous with cell volume, it may come as a bit of a surprise that the very osmotic forces that conspire to induce the pump actually encourage cell shrinkage rather than volumization.
This makes sense, on paper at least. Increase the concentration of solute on one side of a semi-permeable membrane, and water will diffuse down its concentration gradient until the system reaches equilibrium. Likewise, 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 effectively decrease cell volume.
Fortunately, skeletal muscle is well-equipped to deal with this. Through 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 skin-splitting pumps (4).
Understanding how this works isn't just academic; it's fundamental to harnessing the anabolic power of cell volume. Cell volume increases during a muscle pump via the coordinated activity of two transporter proteins located in the cell membrane (4).
In the first step, the sodium-potassium (Na+/K+) ATPase pump moves three sodium ions out of the cell, in exchange for the influx of two potassium ions. Because the concentration of sodium is typically 10-20 times higher outside of cells compared to inside, energy is required in the form of ATP to pump sodium outside the cell, against its concentration gradient.
In the second step, another membrane-associated pump called the sodium-potassium-chloride co-transporter pump (NKCC, for short), simultaneously transports one sodium, one potassium, and two chloride ions from outside the cell to inside the cell.
Doing the math, we find that coordinated action of the Na+/K+ ATPase and NKCC pumps results in a net influx of charged ions into the cell, which increases intracellular osmolarity. As intracellular osmolarity increases relative to the interstitial fluid, extra water is pulled into the muscle, increasing cell volume.
Importantly, the cell volume increase mediated by the NKCC pump is driven by the sodium gradient created by the Na+/K+ ATPase pump (4). You can see how this works in the figure below:
Cell Volume and Amino Acid Transport
The extracellular sodium gradient created by the Na+/K+ ATPase pump isn't just important for increased cell volume. Amino acid uptake is also driven by this sodium gradient. To repair trashed muscle tissue, we need to get amino acids inside the cell to turn on protein synthesis. Although all essential amino acids activate protein synthesis to a certain extent, leucine is the most potent trigger.
Transport of leucine into the cell occurs via a "Tertiary Active Transport" mechanism that I described in detail in this article. For our purposes here, the exact molecular details of this process are less important than the big-picture.
To kick-off the muscle growth and repair process after intense training, we need to get leucine inside the cell. Leucine uptake is driven by cell volume and dependent on the sodium gradient induced by the Na+/K+ ATPase (5).
At this point, you might notice a trend here: as with increased cell volume, amino acid uptake is dependent on sodium, potassium, ATP, and water at the most basic level.
Cell Volume, Protein Synthesis and Protein Breakdown
Cell swelling inhibits protein breakdown and stimulates protein synthesis in a number of cell types (6-8) including skeletal muscle (9, 10). Because the act of training hard turns on protein synthesis as well as protein degradation (11), we're essentially fighting a war against protein breakdown after every single workout.
Consistently shift this balance toward protein synthesis and away from protein breakdown and we win the war on muscle growth, adding new size and strength. Because protein turnover increases substantially in the minutes to hours after training (11), maximizing cell volume with optimal workout nutrition is critical to long-term progress.
Cell Volume Action Plan
Now that we understand how all this works, there are a number of things we can do to harness the anabolic power of cell volume.
1. Get Hydrated
This one is a no-brainer. At the most basic level, proper hydration is needed for optimal cell volume. The ability to activate protein synthesis and suppress protein breakdown during the peri-workout period are both dependent on this. If you're even a little dehydrated, performance and recovery ability will be impaired.
2. Optimize Electrolytes
In order to get water inside cells to increase cell volume, we also need osmolytes, which are osmotically active molecules that pull water into the cell. To that end, maintaining optimal levels of sodium, magnesium, and potassium are critical. (Also of honorable mention are chloride, calcium, and phosphorous.)
As we learned above, sodium and potassium are required for cell volumization and amino acid uptake. At a minimal level, don't shy away from sodium pre- or post-training. Blood volume is highly dependent on sodium levels, and if you're sodium-depleted, the pump you get while training will be almost non-existent.
Also, be sure to regularly consume potassium-rich foods. Potatoes, broccoli, bananas, and squash, to name a few, are excellent potassium sources. Function of the Na+/K+ ATPase (12) and NKCC (13) pumps is also dependent on magnesium, so if you have a deficiency here ( and many people do), cell volumization will be compromised. Regular ZMA® supplementation can prevent a deficiency to keep this cell volume machinery running like a well-oiled machine.
3. Creatine Monohydrate, the Original Cell Volumizer
It's hard to have a discussion on cell volume without mentioning creatine, which is stored in muscle cells as phospho-creatine and supplies a phosphate group to regenerate ATP during high intensity contractions.
Creatine supports cell volumization via direct and indirect mechanisms. As an important muscle osmolyte, creatine directly increases cell volume by pulling additional water into the cell when it's absorbed.
Creatine also augments cell volume indirectly. We learned above that the Na+/K+/ ATPase pump uses energy in the form of ATP to move sodium outside the cell, against its concentration gradient. This function is so important for life itself that upwards of 30% of total cellular ATP is used just to keep the Na+/K+ ATPase pump running.
Creatine therefore indirectly augments cell volume by increasing the supply of high-energy phosphate to regenerate ATP. Five grams of creatine per day will work nicely here to augment cell volume.
4. Properly Timed Workout Nutrition
Nutrient timing during the peri-workout period can make or break your ability to recover and improve, and a number of excellent articles have been written on this subject here at T Nation.
In considering workout timing from a macronutrient standpoint, the usual best-practices apply. Amino acids are in and of themselves osmolytes that when transported into cells pull in additional water, increasing cell volume.
Insulin not only activates amino acid transport, but also increases cell volume by inducing glucose uptake. While macronutrient timing is important, there are additional considerations to be made in order to maximize peri-workout cell volume potential:
Pre-Workout (45 minutes out): Ingest functional carbs such as highly-branched cyclic dextrin to 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.
As mentioned above, the Na+/K+ 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.
Pre-Workout (15 minutes out) and during workout: Continue with 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 critical to promote maximal nutrient uptake and cell volume.
To take the guesswork out of this, use a product specifically designed for this purpose, 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 is also useful here, and in vitro evidence suggests that this may be the ideal time to take it. Creatine uptake efficiency may increase in response to the increased interstitial osmolarity that causes a muscle pump during training (14).
Post-Workout: After a balls-out training session, you need protein, water, and rest. Another pulse of protein hydrolysates will top off the nitrogen tanks to promote continued protein synthesis. From a cell volume standpoint, continue drinking water with electrolytes. (This is the time where many drop the ball, as the last thing you tend to think about after a brutal training session is chugging a bunch of water. Maintain. Hydration.)
5. Maximize Mechanical Tension
While cell volumization is a fundamental driver of muscle growth and recovery, the real magic happens when a volumized muscle is placed under a great deal of mechanical tension.
Part of the mechanism by which cell swelling activates protein synthesis is via increased tension on the cytoskeleton, which directly increases protein synthesis by enhancing mRNA translational efficiency (15, 16). Mechanical tension in response to high-intensity muscle contractions also directly activates amino acid uptake (17), in part by activating the Na+/K+ ATPase pump (18).
By now you can see how training the hell out of a volumized muscle creates a highly anabolic state. Place a volumized muscle under a heavy load with sufficient time-under tension, and you increase amino acid uptake and protein synthesis. Throw in perfectly executed workout nutrition and you have an anabolic orgy.
1. Lindinger MI, Spriet LL, Hultman E, Putman T, McKelvie RS, Lands LC, et al. Plasma volume and ion regulation during exercise after low- and high-carbohydrate diets. Am J Physiol 1994;266:R1896-R1906.
2. Lundvall J, Mellander S, Sparks H. Myogenic response of resistance vessels and precapillary sphincters in skeletal muscle during exercise. Acta Physiol Scand 1967;70:257-68.
3. Lundvall J. Tissue hyperosmolality as a mediator of vasodilatation and transcapillary fluid flux in exercising skeletal muscle. Acta Physiol Scand Suppl 1972;379:1-142.
4. Lindinger MI, Leung M, Trajcevski KE, Hawke TJ. Volume regulation in mammalian skeletal muscle: the role of sodium-potassium-chloride cotransporters during exposure to hypertonic solutions. J Physiol 2011;589:2887-99.
5. Baird FE, Bett KJ, MacLean C, Tee AR, Hundal HS, Taylor PM. Tertiary active transport of amino acids reconstituted by coexpression of System A and L transporters in Xenopus oocytes. Am J Physiol Endocrinol Metab 2009;297:E822-E829.
6. Haussinger D, Hallbrucker C, vom DS, Decker S, Schweizer U, Lang F, et al. Cell volume is a major determinant of proteolysis control in liver. FEBS Lett 1991;283:70-2.
7. Haussinger D, Hallbrucker C, vom DS, Lang F, Gerok W. Cell swelling inhibits proteolysis in perfused rat liver. Biochem J 1990;272:239-42.
8. Stoll B, Gerok W, Lang F, Haussinger D. Liver cell volume and protein synthesis. Biochem J 1992;287 ( Pt 1):217-22.
9. Low SY, Rennie MJ, Taylor PM. Involvement of integrins and the cytoskeleton in modulation of skeletal muscle glycogen synthesis by changes in cell volume. FEBS Lett 1997;417:101-3.
10. Low SY, Rennie MJ, Taylor PM. Signaling elements involved in amino acid transport responses to altered muscle cell volume. FASEB J 1997;11:1111-7.
11. Drummond MJ, Dreyer HC, Fry CS, Glynn EL, Rasmussen BB. Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling. J Appl Physiol 2009;106:1374-84.
12. WHANG R, WELT LG. Observations in experimental magnesium depletion. J Clin Invest 1963;42:305-13.
13. Flatman PW. The effects of magnesium on potassium transport in ferret red cells. J Physiol 1988;397:471-87.
14. Alfieri RR, Bonelli MA, Cavazzoni A, Brigotti M, Fumarola C, Sestili P, et al. Creatine as a compatible osmolyte in muscle cells exposed to hypertonic stress. J Physiol 2006;576:391-401.
15. Kimball SR, Farrell PA, Jefferson LS. Invited Review: Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. J Appl Physiol (1985 ) 2002;93:1168-80.
16. Goldspink DF. The influence of immobilization and stretch on protein turnover of rat skeletal muscle. J Physiol 1977;264:267-82.
17. Vandenburgh HH, Kaufman S. Stretch-induced growth of skeletal myotubes correlates with activation of the sodium pump. J Cell Physiol 1981;109:205-14.
18. MacKenzie MG, Hamilton DL, Murray JT, Taylor PM, Baar K. mVps34 is activated following high-resistance contractions. J Physiol 2009;587:253-60.