Scientific Nutrition Update 44: Arginine Precursors, Macrophages, and Recovery


This episode is a request from a fan of the site.  They wanted to know whether arginine precursors may help with recovery by interacting with macrophages.  This is a little bit heavier science than many of my episodes, but it was interesting to me and I hope it will be interesting to you too.

Script (remember I ad-lib and go off script):

For today’s episode I am going to talk about a request from Dino Tassigianis.  Dino’s question was about whether or not arginine precursors may help with recovery by interacting with macrophages.  Just a warning we are diving deeper into biochemistry and more complicated biochemistry than normal, but I thought it was fascinating when I was researching it so you may enjoy it.


So we are going to need to define some of these terms to make this episode make any sense at all.  First of all macrophages, they are large phagocytic cells that help modulate inflammation, they can be both anti-inflammatory and pro-inflammatory and as such have been indicated as an important modulator of muscular recovery.  Now it is important to remember that muscular growth requires a certain degree of inflammation, that is likely why anti-inflammatories like advil (ibuprofen) seem to reduce muscular growth. However, when the inflammation passes a certain point then it becomes counterproductive, and macrophages are an important regulator of this balance.  However these are some of the most complex interactions I’ve seen with a huge number of regulators, including feedback inhibitions and more. I am going to do my best to summarize what I have learned, but I feel like I have not fully cracked it so if you know anything more about this please email me at, I would appreciate the help.  


So what did I find to answer Dino’s question.  Well it’s complicated. First of all there is a specific reason that he specifically asked about arginine precursors instead of just arginine supplementation.  Arginine supplementation has been pushed by some less than scrupulous supplement companies for its potential benefit to increase nitric oxide and therefore blood flow.  However, oral supplementation of arginine is functionally worthless. The doses required to see a measurable change tend to cause intense gastrointestinal distress. Obviously this is counterproductive.  So that is why Dino asked about arginine precursors instead, hoping that after they were broken down they would increase arginine levels, and interact with the macrophages in a way that could promote recovery.  So there is a couple things we need to look at, including how these precursors are broken down, and then what levels of both the precursor and arginine itself have on macrophages.


So let’s take a look at citrulline which is an arginine precursor.  When it is it is primarily part of the Urea cycle and through the urea cycle can influence levels of plasma arginine.  It is not a common dietary amino acid, being found primarily in watermelon, so most normally it is produced in your body from either arginine or to a greater degree glutamine.  In the urea cycle normally arginine is converted to ornithine and then subsequently to citrulline. The final part of the cycle and what matters to us here is that citrulline can bind with aspartate, which is then degraded to arginine.  So we could expect supplementation of citrulline to be able to increase levels of arginine. What makes this even more interesting is citrulline can be converted to arginine as part of the nitric oxide cycle. I’ll explain why that is important when we get back to our discussion of macrophages.  Just tuck that knowledge away for now.


Before I return to the macrophages which are one of the proposed mechanisms I wanted to get an idea for what the literature actually suggested about the underlying question here, namely can precursors such as citrulline be valuable in recovery.  Short answer is it seems like yes, though it likely needs more investigation. There was a study done on 41 trained men that looked at whether citrulline could help with muscular performance and soreness. What they found was that those in the citrulline group had: significantly lower soreness at both 24 and 48 hours, and significantly more repetitions performed.  The way the study was done was they had to do 8 total sets at 80% of their predetermined 1 repetition max for a total of eight sets. From the third set on through the eighth the group supplementing with citrulline did significantly more repetitions. By the eighth set the group that got citrulline was doing twice as many reps as the placebo group, (not super meaningful because the number of reps had decreased pretty significantly by then).  These results suggest to me that citrulline may not just be valuable in recovery, but also in anaerobic performance. This is a big deal, because many much marketed supplements fail to show this kind of improvement.


So now that we know that it can work we need to turn our attention back to macrophages to determine if that is a reasonable mechanism.  This is where I get especially befuddled, but I will do my best. Citrulline by itself when placed in macrophages seems to inhibit arginase activity, which is part of the urea acid cycle and would normally convert arginine to ornithine.  So citrulline definitely can change pathways in macrophages, the question then becomes whether the supplementation modifies the pathways in a way that promotes recovery. To this I kinda have to shrug my shoulders and say probably? We see the evidence in the literature that seems to suggest that in practical applications that it does help, but looking at these pathways in specific it is hard to determine, especially since muscular recovery is such a complicated process requiring both inflammation and anti-inflammation at different points.  However, it is important to note that for recovery the macrophages seem to as needed utilize either the urea cycle or the nitric oxide synthase pathway, and so supplementation of citrulline which increases the amount of arginine available for this, to me seems as though it could reasonably assisting macrophagic based muscular recovery.


I am optimistic about the potential of citrulline for a couple of reasons.  First of all let’s start with the fact that injected arginine has already been indicated as potentially useful for accelerating wound healing and increasing blood flow.  Then we look at the fact that oral citrulline can raise plasma arginine levels it would seem promising that it would then also help with recovery and healing and blood flow.  We also have one well done study suggesting it reduces soreness and improves performance which again suggests to me that it is having what I call a “real effect”. I make the distinction of a real effect because some nutraceutical companies and people peddling certain diets can get too bogged down in certain pathways and miss the forest for the trees, I always like to start with the pathways but without confirmation from a study that showed the actual effect, I get very nervous.  Finally as to whether or not this process is mediated at least in part by macrophages all I can say is most likely yes. We know for a fact that levels of both arginine and citrulline in these cells interact with metabolic pathways in them, and that they are important for recovery. Combining those pieces of information suggests to me that macrophages are likely at least part of the story of how citrulline could increase recovery. Now I focused only on citrulline here, rather than say ornithine, for two reasons 1. Citrulline was a little bit better studied, and 2. I only really had time to focus on one precursor in this episode.  


Remember I am not fully convinced that I understand this and welcome any and all input.  Please feel free to send me an email if you think I made a mistake or you know more about this, I would love to learn more it was a really interesting pathway.  Also I want to make sure you guys realize that often you guys are learning this stuff right alongside me. Many of these episodes I know very little about the topic until I do my research.  That’s why it takes me a couple hours of work to prep each short podcast episode. If you would like your own questions answered then send me a voice message on Anchor or shoot me an email at If you learned something new in this episode please consider sharing it with a friend and thank you for tuning in and thank you to Dino for giving me this great project.  


Bibliography (I may not directly address these studies in the episode but I looked at them and thought they might be valuable):


Acute l-arginine supplementation increases muscle blood volume but not strength performance. 2012. Applied Physiology, Nutrition, and Metabolism 37(1):115-26.

Barbul A, Lazarou SA, Efron DT, Wasserkrug HL, Efron G. 1990. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 108(2):7.

Comalada M, Yeramian A, Modolell M, Lloberas J, Celada A. 2012. Arginine and macrophage activation. Methods Mol Biol 844:223-35.

Dumont N and Frenette J. 2010. Macrophages protect against muscle atrophy and promote muscle recovery in vivo and in vitro: A mechanism partly dependent on the insulin-like growth factor-1 signaling molecule. The American Journal of Pathology 176(5):2228.

Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, Schuler G. 2000. Correction of endothelial dysfunction in chronic heart failure: Additional effects of exercise training and oral L-arginine supplementation. Journal of the American College of Cardiology 35(3):706-13.

Hamidzadeh K, Christensen SM, Dalby E, Chandrasekaran P, Mosser DM. 2017. Macrophages and the recovery from acute and chronic inflammation. Annual Review of Physiology 79(1):567-92.

Lerman A, Burnett JC, Jr, Higano ST, McKinley LJ, Holmes DR, Jr. 1998. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 97(21):2123-8.

M A Tayeh and M A Marletta. 1989. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. tetrahydrobiopterin is required as a cofactor. Journal of Biological Chemistry 264(33):19654-8.

Moinard C, Nicolis I, Neveux N, Darquy S, Bénazeth S, Cynober L. 2008. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: The citrudose pharmacokinetic study. Br J Nutr 99(4):855-62.

Morris SM. 2006. Arginine: Beyond protein. Am J Clin Nutr 83(2):512S.

Pekarova M and Lojek A. 2015. The crucial role of l-arginine in macrophage activation: What you need to know about it. Life Sci 137:44-8.

Pérez-Guisado J and Jakeman PM. 2010. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res 24(5):1215-22.

Rytlewski K, Olszanecki R, Korbut R, Zdebski Z. 2005. Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia. Eur J Clin Invest 35(1):32-7.

Shearer JD, Richards JR, Mills CD, Caldwell MD. 1997. Differential regulation of macrophage arginine metabolism: A proposed role in wound healing. Am J Physiol 272(2 Pt 1):181.

Vanita Gupta, Asheesh Gupta, Shalini Saggu, Harish M. Divekar, K. Grover, Ratan Kumar. 2005. Anti-stress and adaptogenic activity of l-arginine supplementation. Evidence-Based Complementary and Alternative Medicine 2(1):93-7.

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