The Optimal Timing of Leucine Consumption
Anabolism is defined as the synthesis of complex molecules from more simple ones. While there are many different anabolic pathways in the human body, the one that has the greatest impact on muscle growth involves the synthesis of complex muscle proteins from simpler building blocks, known as amino acids, where the accumulation of muscle protein stemming from this anabolic process ultimately drives muscle growth.
In terms of diet, it is well established that muscle protein levels can be increased considerably after consuming the amino acid leucine, especially during and after weight training. This occurs primarily because leucine consumption activates the nutrient-sensing molecule mTOR— which directly turns on muscle protein synthesis while inhibiting muscle protein breakdown, causing muscle protein accumulation that drives muscle growth.
The direct link between leucine and muscle anabolism has engendered the idea that more leucine consumption should be better for muscle growth. Unfortunately, that just is not the case— as leucine consumption also triggers additional anabolic processes that effectively lower the amount of available energy to the muscle cell, making the consumption of leucine before exercise detrimental to performance. In addition, leucine intake before training alters brain neurochemistry, resulting in sluggishness that hinders performance.
As a result, leucine supplementation protocols must take into account the temporal influence of ingestion in order to optimize muscle growth, while also allowing for ample production of energy and the right neurotransmitters for maximum performance in the gym.
Leucine Consumption During and After Working Out Stimulates Muscle Growth
Several studies have shown mTOR activation by leucine intake directly after resistance exercise. One study by Walker et al.1 showed that leucine consumption shortly after working out increased mTOR activity for several hours post-workout, leading to greater muscle protein synthesis as compared to an exercised group that was not fed leucine. A second investigation by Pasiakos et al.2 demonstrated that consumption of leucine immediately after exercise increased muscle protein synthesis by as much as 33 percent.
At the same time as leucine consumption enhances muscle protein synthesis after resistance training, it also decreases muscle protein breakdown during and following exercise by activating mTOR 3, which turns off the enzyme AMPK.4 AMPK [AMP-activated protein kinase] is the muscle cell’s energy gauge that promotes the breakdown of protein into amino acids when muscle cell energy is low, so the amino acids can be used for energy to restore the cell’s energy status. Therefore, leucine consumption during and after workouts prevents the AMPK-driven breakdown of lean body mass, which enhances the hypertrophic response of muscle tissue.
Pre-Workout Leucine Decreases Muscle Cell Energy
As previously mentioned, the anabolic effect of leucine is not always best for performance in the weight room. This is especially true when consuming leucine before hitting the gym, as leucine activates the conversion of glucose into glycogen while simultaneously preventing the breakdown of glycogen into glucose.5 Both of these outcomes considerably reduce the available energy necessary for muscular contraction. Of course, reduced muscular contraction will decrease strength output, which at the end of the day compromises the ability to gain muscle mass and strength.
Too Much Leucine Likely Inhibits Insulin-Driven Muscle Growth
Insulin is the most potent muscle-building hormone produced in the human body, possessing the ability to drastically increase muscle protein synthesis and enhance muscle growth.6 Insulin achieves this muscle-building effect by binding to the insulin receptor and setting off a cascade of signaling events that eventually activates the enzyme mTOR, triggering muscle growth.7,8 However, insulin signaling is very sensitive to overstimulation, where too much insulin signaling can rapidly trigger negative feedback mechanisms that turn down insulin-driven muscle growth.
In addition to the well-known influence that glucose has on insulin secretion and activity, one of the more potent insulin activators is leucine. Interestingly, several studies have shown that insulin resistance can occur with increased amino acid consumption, especially the branched-chain amino acid leucine.9,10 The exact mechanism by which leucine modulates insulin sensitivity is currently unclear. The decreased insulin sensitivity may be associated with greater insulin secretion induced by leucine11,12, potentially inducing insulin resistance. Of course, insulin resistance from too much leucine consumption would reduce all of insulin’s anabolic properties, meaning a decrease in muscle protein accumulation and therefore muscle growth.
Leucine Consumption Before Your Workout Promotes Sluggishness and Fatigue
The central nervous system (CNS), composed of the brain and spinal cord, serves as the main “processing center” for the entire nervous system that controls all the workings of your body. Neurons, or nerve cells, are the core components of the CNS that function to receive and confer all of this body-regulating information by neuronal signaling. Each neuronal signal is converted at the nerve ending or synapse into chemical signaling via neurotransmitters that diffuse across the synapse to adjacent neurons— triggering further signaling down the neuron, eventually controlling many different bodily functions.
Serotonin is a neurotransmitter secreted within the neuronal synapse that induces sleep and drowsiness. Intense exercise has been shown to increase the release of serotonin in the brain, putatively contributing to exercise-induced fatigue. Initially, it was thought that the increase in serotonin alone triggered fatigue. However, it turns out that greater fatigue from exercise is influenced more specifically by an increase in the ratio of serotonin to another neurotransmitter known as dopamine.13 The neurotransmitter dopamine has well-defined roles including increased mental arousal, improved motor control and greater levels of motivation, which all tend to improve exercise performance.
Interestingly, a recent study by Choi et al.14 showed that leucine competitively inhibits dopamine production by preventing the uptake of the dopamine-precursor tyrosine into the brain. Since greater brain dopamine function improves physical performance, the finding that leucine reduces dopamine levels in the brain highlights why leucine consumption, especially before exercise when motivation and energy levels are paramount, may have a detrimental influence on physical performance.
In conclusion, leucine’s capacity to trigger anabolic processes, such as muscle growth and glycogen production, makes the timing of leucine consumption very important. While leucine consumption during and after lifting weights effectively prevents muscle breakdown while enhancing post-workout muscle protein synthesis, consuming leucine before your workout appears to have several drawbacks that negatively influence exercise performance, indicating that leucine consumption before training likely prevents optimal function and achievement.
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 biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. 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 scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.
1. Walker DK, Dickinson JM, et al. Exercise, amino acids, and aging in the control of human muscle protein synthesis. Med Sci Sports Exerc 2011;43, 2249-2258.
2. Pasiakos SM, McClung HL, et al. Leucine-enriched essential amino acid supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis. Am J Clin Nutr 2011;94, 809-818.
3. Manders RJ, Koopman R, et al. The muscle protein synthetic response to carbohydrate and protein ingestion is not impaired in men with longstanding type 2 diabetes. J Nutr 2008;138, 1079-1085.
4. Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda) 2008;23, 160-170.
5. Di Camillo B, Eduati F, et al. Leucine modulates dynamic phosphorylation events in insulin signaling pathway and enhances insulin-dependent glycogen synthesis in human skeletal muscle cells. BMC Cell Biol 2014;15, 9.
6. Hillier TA, Fryburg DA, et al. Extreme hyperinsulinemia unmasks insulin's effect to stimulate protein synthesis in the human forearm. Am J Physiol 1998;274, E1067-1074.
7. Biolo G, Declan Fleming RY and Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest 1995;95, 811-819.
8. Guillet C, Prod'homme M, et al. Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. Faseb J 2004;18, 1586-1587.
9. Newgard CB, An J, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009;9, 311-326.
10. Tremblay F, Lavigne C, et al. Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 2007;27, 293-310.
11. Filiputti E, Rafacho A, et al. Augmentation of insulin secretion by leucine supplementation in malnourished rats: possible involvement of the phosphatidylinositol 3-phosphate kinase/mammalian target protein of rapamycin pathway. Metabolism 2010;59, 635-644.
12. Yang J, Chi Y, et al. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev 2010;68, 270-279.
13. Acworth I, Nicholass J, et al. Effect of sustained exercise on concentrations of plasma aromatic and branched-chain amino acids and brain amines. Biochem Biophys Res Commun 1986;137, 149-153.
14. Choi S, Disilvio B, et al. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids 2013.