Written by Michael J. Rudolph, Ph.D.
08 June 2021






The Best Post-Workout Muscle Growth Stack


By Michael J. Rudolph, Ph.D.


The right mixture of ingredients in your post-workout stack will precisely target the function of specific protein molecules within the body, triggering an anabolic environment that will generate massive muscle growth.


Ever since the renowned physicist Erwin Schrödinger wrote his groundbreaking book What Is Life? in 1944, intimating that all of life emanated from the function of molecules, the quest to understand life at its most fundamental level began. The interest in molecular function brought on by Schrödinger’s book led to the discovery of the chemical structure of the DNA molecule in 1953, which essentially opened up the floodgates for the molecular revolution. Since then, the molecular revolution has led to the discovery, and characterization, of many different biomolecules found within the human body.


All of this wealth of molecular information spawned a much deeper understanding of human biochemistry, and physiology, leading to cures for all sorts of different diseases. The abundance of molecular knowledge that is now available also describes, to some degree, most protein molecules within the body revealing how these protein molecules function and how they can also be controlled by certain chemical compounds. Many different compounds have been discovered that regulate the function of certain protein molecules in the body, producing an anabolic effect that potently enhances the hypertrophic response to weight training.


Cutting-edge molecular science has revealed that the simultaneous ingestion, or stacking, of certain compounds immediately after weight training can enhance muscular growth to remarkably high levels. The right mixture of ingredients in your post-workout stack will precisely target the function of specific protein molecules within the body, triggering an anabolic environment that will generate massive muscle growth.


Boost Muscle Growth WithLeucine and Prevent Muscle Breakdown With HMB


Leucine intake has been shown to directly stimulate muscle protein synthesis and inhibit muscle protein breakdown ultimately promoting muscle growth, by directly activating the nutrient-sensing molecule mTOR. The muscle-building effect of leucine consumption has been shown in several studies to be most potent after resistance training. In fact, one study by Walker et al.1 showed that leucine consumption, immediately after working out, increased mTOR activity for several hours after training leading to greater muscle protein synthesis when compared to a second group that did not take leucine post-workout.


In addition to leucine’s ability to promote muscle growth, one of its primary metabolites, HMB, also triggers considerable muscle growth. However, HMB positively influences muscle growth by attenuating muscle protein breakdown instead of stimulating muscle protein synthesis like leucine does. HMB produces this different effect by reducing the production of the muscle-degrading molecule atrogin-1, effectively preventing2 the breakdown of muscle protein and thus muscular atrophy.3 In a study showing the influence of HMB on muscle protein breakdown, it was found that 3,000 milligrams of HMB increased muscle protein synthesis rather weakly, but attenuated muscle protein breakdown by a whopping 57 percent.4 Importantly, a second study showed that the ability of HMB to reduce muscle protein catabolism does actually increase muscle growth and strength, when combined with resistance training.5 As a result of the complementary muscle-building functions of leucine and HMB, their co-ingestion will not only drive the synthesis of new muscle protein but will also prevent the breakdown of existing muscle protein, resulting in extraordinary levels of muscle hypertrophy.


Build Muscle With Creatine


Creatine monohydrate is one of the most well characterized muscle-building supplements, with many of its molecular targets clearly defined. Altogether, the body of evidence shows that creatine supplementation increases power output during intense exercise while also stimulating muscle hypertrophy.6 The unique capacity of creatine to boost size and power stems, in part, from creatine’s ability to function as a primary energy storage molecule that rapidly reverses the depletion of muscle cell energy (ATP) during muscular contraction ultimately recharging energy levels within the muscle cell, prolonging muscular contraction for superior muscle growth and performance.7 Creatine also potently drives muscle growth by triggering several different molecular mechanisms, including the stimulation of muscle cell formation8 and increased muscle protein synthesis.9 


Prevent Muscle Atrophy With Leucine, Creatine Monohydrate and HMB Stack


Perhaps the most potent muscle-destroying protein discovered during the molecular revolution is the protein molecule myostatin. This muscle-depleting molecule prevents muscle growth by inhibiting the formation of new muscle fibers10, while also decreasing mTOR-driven muscle protein synthesis.11 While many reports in the scientific literature clearly show the independent muscle-building effects of leucine, creatine monohydrate and HMB, the combined use of all three compounds has only recently been shown to reduce the negative influence of myostatin on muscle growth. A study by Mobley et al.12 showed that a mixture containing leucine, calcium HMB and creatine monohydrate reversed myostatin-induced atrophy in isolated muscle cells by preventing the inhibition of newly formed muscle fibers, and therefore muscle growth. This compound mix shows great potential to inhibit myostatin’s hold on muscle growth, and a post-workout formula with all three ingredients should trigger the formation of new muscle fibers for unprecedented levels of muscle growth.


Pump Up With Betaine


Betaine – also known as trimethylglycine – is a natural compound found in the cell that functions as an osmolyte, protecting the cell against dehydration by increasing cellular water retention through osmosis. The ability of betaine to function as an osmolyte contributes to muscle hypertrophy by causing the muscle fiber to swell. Research has shown that muscle cell swelling stimulates protein synthesis and decreases protein breakdown, resulting in muscle growth.13,14


In addition to betaine’s ability to counter dehydration and trigger musclehypertrophy, betaine also plays a key role in the biosynthesis of creatine – implying that betaine should mimic the muscle-building effects of creatine to some degree. Indeed, it has been shown that betaine ingestion does significantly increase anaerobic power in the bench press and squat— conceivably because of the capacity of betaine to increase creatine levels within muscle tissue.15


Unchained Muscle Growth: Vitamin D3 Stacked With Creatine


Vitamin D used to be thought of as just another vitamin important for matters like bone health. However, a more contemporary understanding of this vitamin uncovered during the molecular revolution has found that vitamin D is actually a powerful prohormone that drives muscle growth by regulating the expression of many different genes within the human genome.16,17 Some of the muscle-promoting genes regulated by vitamin D are involved in the production and function of testosterone.18


Another gene controlled by vitamin D enhances insulin sensitivity, in part, by increasing expression of the insulin receptor gene. The increase in insulin receptor expression results in more insulin receptors on the surface of the muscle cell, which causes a more sensitive signaling response to insulin. Because insulin function boosts muscle growth, the enhanced insulin response brought on by vitamin D can, in due course, deliver more muscle growth.


Other scientific evidence has also shown the capacity of vitamin D3 to increase insulin receptor levels within the muscle cell, providing a more robust anabolic response to leucine intake. A study by Salles et al.19 looked at the influence that vitamin D3 the most active form of vitamin D in humans had on leucine-activated insulin signaling in muscle cells. Since muscle protein synthesis is positively regulated by leucine consumption, the researchers wanted the see if vitamin D3 could enhance leucine activation of the insulin pathway. The results of this investigation showed that vitamin D3 enhanced the ability of leucine to activate insulin signaling while also increasing the rate of muscle protein synthesis. This investigation also demonstrated that this increase in insulin signaling and muscle protein production was due primarily to the increased expression of the insulin receptor gene which increased the number and activity level of insulin receptors embedded within the muscle cell, fostering a greater anabolic response within the muscle cell. Altogether, the science clearly reveals that vitamin D3 can potentiate the impact of insulin, and leucine, on muscle growth making the stacking of these two compounds a fantastic way to gain lean muscle. 


Advanced mTOR-Driven Muscle Growth With Phosphatidic Acid


Phosphatidic Acid (PA) is a phospholipid found in the cell membrane involved in many different cell-signaling cascades, including one signaling pathway that stimulates muscle growth. While it has clearly been established that mTOR is necessary for the hypertrophic response to resistance training, the activation of mTOR has previously been proposed to occur through the IGF-1 signaling cascade. However, several scientific studies conclusively illustrate that an increase in PA is responsible for the activation of mTOR signaling in response to resistance exercise, without the need for IGF-1 activity. A study by O’Neill et al.20 showed that incubating isolated muscle cells with PA is sufficient to induce an increase in mTOR signaling. In the same study, the researchers also showed that the activation of mTOR by PA occurred even when the isolated muscle cells had their IGF-1 signaling pathway chemically inhibited— demonstrating that PA activation of mTOR occurred separately from IGF-1 signaling. One more interesting finding from this study relates to the fact that mechanical stress put on the muscle cell from weightlifting activates the enzyme phospholipase D, which catalyzes the production of PA.


Since PA increases mTOR-driven muscle protein synthesis, a group of researchers tested whether PA could also increase muscular size and strength. In this study by Hoffman et al.21, researchers looked at the influence that PA had on strength in 16 test subjects with adequate weightlifting experience. The subjects were split into two groups, with one group receiving 750 milligrams of PA per day and the other group taking a placebo. During the experiment, each subject lifted weights four days a week at 70 percent of their one-repetition maximum (1RM) for all lifts during the entire eight-week trial period. Each subject was tested for strength and body composition at the end of the experimental period. The results showed that subjects ingesting PA demonstrated a 12.7 percent increase in squat strength and a 2.6 percent increase in muscle mass— while subjects consuming a placebo showed much less improvement in squat strength and virtually no increase in muscle mass.


So, taking everything into consideration, the results of these studies indicate that the activation of mTOR can be caused by an insulin-independent way by PA and an insulin-dependent fashion by compounds such as leucine. Thus, stacking PA with leucine should coordinately activate mTOR with, and without, requiring insulin producing extraordinary mTOR function that drives superior lean muscle growth.


For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a research scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biological effects of exercise as a fellow at Harvard Medical School and Columbia University. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK – leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a Senior Scientist working at the New York Structural Biology Center where he investigates the molecular nature of human illness and disease.



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