My Cart


science nutrition blog

science nutrition <strong>blog</strong>

New Study!

By: Robert A. Schinetsky


For decades we’ve known that to get big and strong, you have to lift heavy things multiple times, relatively frequently. However, only recently have sports scientists begun to uncover what is taking place at the cellular level that drives muscle growth.

Suffice it to say we are in the midst of a “golden era” for exercise science, particularly in regards to muscle hypertrophy, as scores of studies have been published in recent years investigating the ins and outs of muscle growth and human performance. 

From this constant research effort, scientists have identified three main mechanisms of muscle hypertrophy in[1]:

- Mechanical tension (i.e. weight on the bar)

- Muscle damage

- Metabolic stress

exercise induced hyperaemia

However, a new systematic review indicates that cellular swelling may be a much more powerful driver of muscle growth than previously thought. 

Before we get into the study and its findings, let’s quickly review what happens when you get a muscle pump.

How Do Muscle Pumps Work?

During resistance training, arterial blood flow to the working muscles increases while muscle contractions cause compression of veins. This creates a scenario similar to turning a faucet on high, attaching balloon to it that has pinhole on the end.

The water will rush in, and since, the exit (“hole) is so small, the balloon continues to fill, getting bigger and bigger.

The same thing happens in your muscles. More and more blood flow is being pumped to the muscle, yet due to repeated muscle contractions, the “exit” (veins”) are restricted, creating a “pooling” of blood in the muscle along with tremendous cellular swelling and one hell of a muscle pump.

The body perceives this sudden swelling as a threat to the structural integrity of the cell and its survival. In response to this threat, the cell enacts various anabolic processes (including upregulation of protein synthesis) while simultaneous downregulating assorted catabolic processes, to make a bigger, stronger, more resilient muscle cell.[2]

So, maybe all those gym bros who were chasing the pump for years and years in the gym were onto something?

Still, the common belief among researchers was that cellular swelling and various other metabolic stress factors weren’t directly responsible for muscle growth. They were either “permissive” of anabolism or a “secondary” factor due to performing greater amounts of mechanical work, with the thinking being that lifting heavier weight (increased mechanical tension) would lead to higher levels of metabolites.[3

However, recent studies suggest that cellular swelling and metabolites may be an independent factor of muscle hypertrophy, not merely a supporting cast member or by-product of heavy lifting.[4]

A new review published in Nutrition set out to investigate the role various cell swelling supplements have on muscle growth.[5] 

3 Ways to Increase Cellular Swelling and Get a Muscle Pump

Over the years, scientists and supplement companies alike have searched for compounds that are capable of enhancing exercise-induced hyperemia (“the pump”). As you’ve probably seen, there’s no shortage of ingredients and full blown pump pre-workouts from which to choose.

But, not all products are created the same, nor do they all work via the same pathways.

In fact, researchers have identified three main mechanisms by which sports supplements enhance cellular swelling:

- Vasodilators, such as nitric oxide boosters

- Anaerobic energy system ergogenic aids that increase metabolite production, such as β-alanine and creatine

- Osmolytes, such as creatine and betaine.

Let’s take a deeper look into each of these categories to see how it impacts cellular swelling, and potentially muscle growth.


Vasodilation refers to the opening or widening of blood vessels which leads to an increase in blood flow and decrease in blood pressure. A number of compounds, termed vasodilators, have been investigated over the years that promote this expansion of blood vessels and increase in blood flow.

This blood flow-boosting agents are highly sought after by the medical community for their role in promoting cardiovascular health and treatment/prevention of hypertension while the lifting community is primarily interested in their ability to yield massive muscle pumps.

Vasodilators work primarily by increasing nitric oxide in the body, but they can also work by counteracting the vasoconstrictive actions of certain enzymes in the body, such as angiotensin-converting enzyme.

Now, in regards to boosting nitric oxide, supplements accomplish this via one of two distinct pathways in the body -- the NOS-dependent pathway or the NOS-independent pathway.

The NOS-dependent pathway is the one most well-known in fitness circles where l-arginine is converted to NO via a set of Nitric Oxide synthases.[7] Now, a number of arginine-based compounds have been released over the years, yielding mixed results in terms of effectively boosting nitric oxide.

The problem with arginine is that it has rather poor bioavailability in the body, meaning that in order to get any tangible increase in blood flow and cellular swelling, you would have to take rather large doses of it (>10g). However, taking large doses while potentially yielding greater NO production, also comes with the rather unwanted side effect of horrendous GI distress and diarrhea.[8]

Fortunately, scientists have stumbled on an ingredient that is more bioavailable (and effective) than l-arginine as well as one that doesn’t come with horrendous GI distress in L-Citrulline malate.

Composed of L-citrulline (an amino acid found in watermelon) and malic acid (an organic acid naturally occurring in apples, citrulline malate is more efficiently used by the body and not subject to breakdown by arginase, the enzyme that degrades arginine, and ultimately limits nitric oxide production, vasodilation, and muscle pumps.[9]

Advanced molecular Labs Pre-Workout contains 8g of citrulline malate per serving -- the exact same amount shown in clinical trials to improve in repetitions completed and total work performed during multiple sets taken to failure[10,11,12] Other studies note that citrulline malate supplementation enhances oxygen kinetics, time to exhaustion, and total work performed during a high-intensity exercise.

Basically, powerful vasodilators, such as citrulline malate, increase blood flow to the working muscle enabling you to perform higher amounts of work and drive more blood to the muscle, which increases metabolites and cellular swelling. This ultimately leads to better muscle growth and performance.

Ergogenic Aids

A second means by which you can enhance cellular swelling and metabolites is through supplementation with ergogenic aids that improve the body’s performance during anaerobic exercise.

Essentially, supplements that help you train harder, sustain more powerful muscle contractions, and improve resistance to fatigue during workouts can enhance hypertrophy as the more times your muscle can contract under load before succumbing to fatigue, the greater amount of metabolites that will be generated, which should lead to more muscle growth.

Two of the best ergogenic aids on the market, as proven by scientific research, are beta-alanine and creatine.


Known far and wide for its “tingling” sensations, beta-alanine is an non-proteinogenic amino acid that binds with histidine to form carnosine.

“What is carnosine?”, you ask

Carnosine is a powerful intracellular buffer that buffers H+ ions (another metabolite generated from repeated muscle contractions).[13] The more efficiently your body can clear H+, the longer you can train before succumbing to fatigue.

See, as H+ continues to accumulate in skeletal muscle, the lower muscle pH drops, and once the pH drops too low, your muscles lose their ability to completely contract. With elevated levels of carnosine in the muscle (thanks to beta-alanine), energy output capacity is increased allowing for greater amounts of muscle metabolites to be generated, which would lead to a larger increase in the cellular swelling effect.

Additionally, since intracellular acidification (lowering of pH) is known to reduce cell volume [15], by buffering intracellular H+ and slowing the decline in muscle pH, beta-alanine may offer a secondary mechanism by which to enhance cellular swelling.

Now, it should be noted, that beta-alanine really shines when during high-intensity exercise lasting 1-4 minutes. Since the typical set in a hypertrophy workouts lasts 40-50 seconds, beta-alanine is best suited to individuals performing repeated bouts of effort interspersed with minimal rest periods, such as repeated bouts of sprints, triple drop sets in the gym, or running up and down a basketball court.

For this reason, beta-alanine is often combined with the king of ergogenic aids -- creatine monohydrate.

Creatine Monohydrate

Simply put, if there’s one, and only one, supplement you should use if you’re looking to build muscle and strength as quickly as possible, it should be creatine monohydrate.

Creatine is an incredibly powerful ergogenic aid providing a wide range of benefits of athletes of all sports.

First and foremost, creatine enhances ATP production in the body by increasing stores of creatine-phosphate in skeletal muscle. Your muscles only have enough ATP to sustain 5-10 seconds of high level effort, after those are exhausted, the phosphagen system kicks into gear as creatine donates its phosphate group to produce more ATP.[16,17]

This rapid regeneration of energy allows you to continue to train harder before taking a rest, or seeing a substantial drop in work performed. A beneficial “side effect” of this process is a reduction in the need for glycolytic metabolism whereby glycogen is broken down to generate ATP.

Additionally, greater reserves of creatine-phosphate have the potential to buffer H+ ions generated during ATP hydrolysis and anaerobic glycolysis in working muscles, further prolonging your ability to bang out more reps, generating more muscle metabolites and cellular swelling before succumbing to fatigue.[18]

But, we’re not quite done with the ways in which creatine enhances muscle growth via cellular swelling.

It may also support vasodilation as some research indicates supplementation with creatine monohydrate decreases arterial stiffness and systolic blood pressure following resistance-training.[19]

Furthermore, creatine supplementation has also led to improvements in systemic endothelial-dependent microvascular reactivity and skin capillary density and recruitment, suggesting its vasodilatory properties occur independent of muscle metabolite.[20]

Creatine also directly enhances cellular hydration due its osmolytic qualities. With increased intramuscular creatine stores comes an increase in the amount of water stored within the cell. This leads to cell volume expansion, improved hydration, and greater muscle fullness. And, as we’ve noted above, cell swelling can trigger protein synthesis in the body.

Finally, supplementation with creatine upregulates mRNA coding for IGF-1 and mRNA expression of myogenic regulatory factor 4 (MRF4), providing two more mechanisms by which creatine enhances muscle growth.[21,22]

Taken together, creatine enhances muscle growth via multiple mechanisms including osmotic effects (cellular swelling), upregulation of protein synthesis, increased work output, and improvements in strength & power, and possibly even vasodilation. This culminates in performing more reps for more sets, leading to greater accumulation of muscle metabolites, cellular swelling, and mechanical tension.

When combined with beta-alanine, as it is in AML Pre Workout, you get the best of both worlds as creatine enhances performance during high-intensity, short burst activity, while beta-alanine sustains you through prolonged efforts.

The final ergogenic highlighted in the recent study denoting the hypertrophic possibilities of cellular swelling is another powerful performance-enhancer in betaine.


Betaine (trimethylglycine) is a modified amino acid consisting of a molecule of glycine surrounded by three methyl groups. It’s naturally occurring in human body and can be found in a number of foods common in the diet, including spinach, wheat, and sugar beets (from which its name is derived).

Betaine serves two important roles in the body as a methyl group donor and as an osmolyte that regulates fluid balance.[23]

First, betaine methylates homocysteine, a compound capable of inducing oxidative damage in endothelial tissue as well as inflammatory cytokine expression via oxidative stress. Because of these actions, betaine supplementation may indirectly enhance vasodilation and cellular swelling during resistance training.

Following methylation, homocysteine is converted into methionine, one of the amino acids necessary for creatine synthesis in the body.[24] In this way, betaine supports endogenous creatine production and subsequently better athletic performance and muscle growth.

In fact, studies have shown that betaine supplementation leads to increases in muscle mass in resistance-trained men.[23]

Betaine also increases intracellular water[25], which as we stated a few times in this article may enhance muscle growth by way of stimulating muscle protein synthesis.


One last avenue by which an athlete looking to maximize cellular hydration and swelling is one that’s neglected in most pre workouts -- electrolytes.

Electrolytes are essential minerals that help regulate fluid balance in the body as well as muscle function. Sodium often gets the lion’s share of the credit when discussing electrolytes, but there’s two other equally important electrolytes that deserve their own individual time to shine in potassium and magnesium.

These two vital minerals serves as “osmoprotectants” when used alongside other prominent cell-hydrating supplements, such as betaine and creatine monohydrate. These valuable electrolytes help preserve fluid balance in muscle, leading to greater gains in strength as well as increased muscle protein synthesis.

AML Pre-Workout and AML Post-Workout supply efficacious amounts of magnesium citrate and potassium citrate to aid skeletal muscle buffering, thereby improving exercise performance, power and strength. These two electrolytes also promote vasodilation by increasing nitric oxide and prostacyclin leading to improved endothelial function, greater blood flow, and lower blood pressure.[26,27]



Researchers continue to elucidate all of the factors that contribute to muscle hypertrophy. Until now, mechanical tension has been viewed as the primary mechanism by which an athlete grows bigger muscles. However, in light of recent research, it appears that cellular swelling may offer yet another effective means for driving growth.

Is cellular swelling and metabolite training superior to mechanical tension in terms of greater muscle growth? That’s yet to be fully teased out in the literature.

However, there definitely is something to be said for incorporating higher volume work that generates these metabolites and increases cellular swelling to a greater degree than doing heavy weight, low volume work. As such, when performing “metabolite training” or training for the pump, it makes sense to utilize the best pre- and post-workout nutrients that improve your ability to tolerate higher work volumes, thereby creating greater amounts of metabolites and cellular swelling, with the end goal of building bigger muscles.

Advanced Molecular Labs includes the best pre-workout and post-workout supplements for increasing vasodilation, blood flow, and cellular swelling in AML Pre-Workout and AML Post Workout.

AML Pre Workout supplies 2 grams of beta-alanine, 5 grams of creatine monohydrate, and 8 grams of citrulline malate -- all identified to be among the best cellular swelling supplements according to researchers. These same nutrients are also backed by numerous studies documenting their respective ability to enhance athletic performance and resistance to fatigue.

AML Post Workout contains 5 grams of creatine and 2.5 grams of betaine anhydrous along with 5g of Leucine to fully activate the mTOR pathway following training and kickstart the muscle recovery and growth process.




  1. Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. The Journal of Strength & Conditioning Research. 2010;24(10):2857-72.
  2. Schoenfeld BJ, Contreras B. The muscle pump: potential mechanisms and applications for enhancing hypertrophic adaptations. Strength & Conditioning Journal. 2014;36(3):21-5
  3. Dankel SJ, Mattocks KT, Jessee MB, Buckner SL, Mouser JG, Loenneke JP. Do metabolites that are produced during resistance exercise enhance muscle hypertrophy? European journal of applied physiology. 2017;117(11):2125-35
  4. de Freitas MC, Gerosa-Neto J, Zanchi NE, Lira FS, Rossi FE. Role of metabolic stress for enhancing muscle adaptations: Practical applications. World J Methodol. 2017;7(2):46-54. Published 2017 Jun 26. doi:10.5662/wjm.v7.i2.46
  5. Cholewa, J., Trexler, E., Lima-Soares, F., de Araújo Pessôa, K., Sousa-Silva, R., Santos, A. M., Zanchi, N. E. (2019). Effects of dietary sports supplements on metabolite accumulation, vasodilation and cellular swelling in relation to muscle hypertrophy: A focus on “secondary” physiological determinants. Nutrition, 60, 241–251.
  6. Tschakovsky, M. E., Shoemaker, J. K., & Hughson, R. L. (1996). Vasodilation and muscle pump contribution to immediate exercise hyperemia. The American Journal of Physiology, 271(4 Pt 2), H1697-701.
  7. Dennis J. Stuehr; Enzymes of the L-Arginine to Nitric Oxide Pathway, The Journal of Nutrition, Volume 134, Issue 10, 1 October 2004, Pages 2748S–2751S,
  8. Grimble, G. K. (2007). Adverse gastrointestinal effects of arginine and related amino acids. The Journal of Nutrition, 137(6 Suppl 2), 1693S–1701S.
  9. Curis, E., Crenn, P., & Cynober, L. (2007). Citrulline and the gut. Current Opinion in Clinical Nutrition and Metabolic Care, 10(5), 620–626.
  10. Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. The Journal of Strength & Conditioning Research. 2010;24(5):1215-22.
  11. Wax B, Kavazis AN, Luckett W. Effects of supplemental citrulline-malate ingestion on blood lactate, cardiovascular dynamics, and resistance exercise performance in trained males. Journal of dietary supplements. 2016;13(3):269-82.
  12. Wax B, Kavazis AN, Weldon K, Sperlak J. Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightlifters. The Journal of Strength & Conditioning Research. 2015;29(3):786-92
  13. Hobson RM, Saunders B, Ball G, Harris R, Sale C. Effects of β-alanine supplementation on exercise performance: a meta-analysis. Amino acids. 2012;43(1):25-37
  14. Kern BD, Robinson TL. Effects of β-alanine supplementation on performance and body composition in collegiate wrestlers and football players. The Journal of Strength & Conditioning Research. 2011;25(7):1804-15
  15. Fraser JA, Middlebrook CE, UsherSmith JA, Schwiening CJ, Huang CLH. The effect ofintracellular acidification on the relationship between cell volume and membrane potential in amphibian skeletal muscle. The Journal of physiology. 2005;563(3):745-64
  16. Deane CS, Wilkinson DJ, Phillips BE, Smith K, Etheridge T, Atherton PJ. “Nutraceuticals”in relation to human skeletal muscle and exercise. American Journal of Physiology- Endocrinology and Metabolism. 2017;312(4):E282-E99
  17. Bemben MG, Lamont HS. Creatine supplementation and exercise performance. Sports Medicine. 2005;35(2):107-25
  18. Sahlin K. Muscle energetics during explosive activities and potential effects of nutrition and training. Sports Med. 2014;44 Suppl 2(Suppl 2):S167-73.
  19. Sanchez-Gonzalez MA, Wieder R, Kim J-S, Vicil F, Figueroa A. Creatine supplementation attenuates hemodynamic and arterial stiffness responses following an acute bout of isokinetic exercise. European journal of applied physiology. 2011;111(9):1965-71.
  20. de Moraes R, Van Bavel D, de Moraes BS, Tibiriçá E. Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults. Nutrition journal. 2014;13(1):115.
  21. Deldicque L, Theisen D, Bertrand L, Hespel P, Hue L, Francaux M. Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. American Journal of Physiology-Cell Physiology. 2007;293(4):C1263-C71
  22. Hespel P, Op't Eijnde B, Leemputte MV, Ursø B, Greenhaff PL, Labarque V, et al. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. The Journal of physiology. 2001;536(2):625- 33.
  23. Cholewa, J. M., Wyszczelska-Rokiel, M., Glowacki, R., Jakubowski, H., Matthews, T., Wood, R., … Paolone, V. (2013). Effects of betaine on body composition, performance, and homocysteine thiolactone. Journal of the International Society of Sports Nutrition, 10(1), 39.
  24. da Silva RP, Nissim I, Brosnan ME, Brosnan JT. Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am J Physiol Endocrinol Metab. 2008;296(2):E256-61.
  25. Hoffman JR, Ratamess NA, Kang J, Rashti SL, Faigenbaum AD. Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr. 2009;6:7. Published 2009 Feb 27. doi:10.1186/1550-2783-6-7
  26. Effect of magnesium supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Darooghegi Mofrad, Manije, et al. Atherosclerosis, Volume 273, 98-105
  27. Effect of high potassium diet on endothelial function. Blanch N, et al. Nutrition, Metabolism and Cardiovascular Diseases, Volume 24, Issue 9, 983-989.