In case this isn’t commonly known. I was surprised to read that citrulline increases mTOR. “On the other hand, it has been shown that CIT can stimulate the mammalian Target of Rapamycin (mTOR) pathway, independent of insulin, the growth hormone (GH) or type 1 insulin-like growth factor (IGF1), improving muscle protein synthesis (MPS) [[15]”(Combined Effects of Citrulline Plus Nitrate-Rich Beetroot Extract Co-Supplementation on Maximal and Endurance-Strength and Aerobic Power in Trained Male Triathletes: A Randomized Double-Blind, Placebo-Controlled Trial - PMC)]
Yes, The nutrient sensing system activates mTOR when you take citrulline. In the same way that other nutrients activate mTOR. But Citrulline might also have mTOR independent pathways for preserving or building muscle.
A poster from the Gordon Lynch lab:
http://aups.org.au/Proceedings/44/13P/13P.pdf
“Both citrulline and arginine increase mTOR phosphorylation and protein synthetic rate in an in vitro model of starvation. Importantly, mTOR phosphorylation is critical for the protective effects of arginine, but not citrulline, on skeletal muscle. Therefore, citrulline may attenuate muscle wasting in vitro by directly activating proteins downstream of mTOR, such as 4EBP1.”
Citrulline supports healthy muscles in other ways than through mTOR activation. Through increased whole body blood perfusion. Most people know that hypoperfusion is damaging to the brain, but the same goes for the rest of our organs. And aging comes with decreased blood circulation throughout the entire body. Especially when it comes to people with tendencies toward metabolic dysfunction. I think an optimized vascular system is a somewhat overlooked perspective. Therefore, I am glad to see the relatively new interest in the off-target effects of Viagra/Cialis.
“Furthermore, L-citrulline prevented inflammation (LPS) and oxidative stress (H2O2) induced muscle cell wasting. In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS (iNOS) isoform. This discovery of a nutritional modulator of iNOS mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions.”
L-Citrulline Supports Vascular and Muscular Benefits of Exercise Training in Older Adults:
" Evidence continues to emerge on the positive impact of chronic L-CIT on vascular and skeletal muscle function in older adults. L-CIT may improve exercise capacity by upregulating muscular perfusion and subsequent oxygen utilization. Evidence suggests that increased L-ARG and NO availability in skeletal muscle may be a crucial factor in promoting muscle function via PGC-1α stimulation of mitochondrial respiratory capacity. In addition, the action of L-CIT on muscle function also is related to its ability to promote muscle protein synthesis"
3 Likes
Thanks for the info. Citrulline seems like a worthy add despite my desire to reduce supplementation. I won’t take it on rapa day, though.
1 Like
Beet root 
citrulline malate 
though not as bad as beet root (it’s sort of okay with sodium bicarbonate though). I was thinking of getting isosorbide dinitrate or just plain nitroglycerine instead though (they beneficial effect is due to that all these are all nitrate donors)
(oh and they do not work in combination with caffeine!)
Yes, I have seen it mentioned that caffeine and beet juice do not interact well, and that they might cancel out each other’s effect on performance.
-
I’d be grateful If you have human studies to share on the subject?
-
I have read anecdotal reports that some can mix caffeine and beet juice and do well, and others say that they (when mixing) do worse, when it comes to aerobic performance. But I have not read that people do worse (performance-wise) when combining citrulline and caffeine.
-
I know that in my case, too much citrulline before aerobic exercise, decrease my endurance. I get too much blood in my quadriceps, and my legs feel heavy. Some kind of pump that makes running more difficult
1 Like
Take L-Citrulline instead of Citrulline Malate to avoid the sour taste
3 Likes
- I have found a few studies on how caffeine and beet juice might interact. None can be said to be convincing. Some showed no effect from combining them, and one showed a positive effect.
1 Like
Just doing an an analysis / summary of the paper the Joe posted in the first message of this thread:
The Nitric Oxide Power Couple: Beetroot and Citrulline Synergy Boosts Aerobic Power
For endurance athletes, the quest for marginal gains often leads to the supplement cabinet. New research suggests that the “stacking” of two well-known nitric oxide (NO) precursors—L-citrulline and nitrate-rich beetroot extract—may provide a synergistic edge that neither can achieve alone. A 9-week randomized, double-blind, placebo-controlled trial involving 32 trained male triathletes has demonstrated that chronic co-supplementation significantly enhances aerobic power and hints at improvements in maximal strength.
The study’s “Big Idea” centers on dual-pathway nitric oxide production. While the body can synthesize NO via the oxidation of L-arginine (fueled by L-citrulline), it also utilizes the nitrate-nitrite-NO pathway (fueled by beetroot). By hitting both pathways simultaneously over a 9-week period, researchers observed a significant interaction in estimated VO2 max. Triathletes taking the combination of 3 grams of L-citrulline and 2.1 grams of beetroot extract daily showed superior improvements in aerobic power compared to those taking either supplement in isolation or a placebo.
While the aerobic benefits were clear, the impact on strength was more nuanced. The combination group showed significant internal improvements in horizontal jump distance and abdominal endurance (sit-ups) over the 9-week period, though these gains did not reach statistical significance when compared directly against the other groups. Mechanistically, the researchers attribute these gains to improved muscle contractility, better mitochondrial efficiency, and enhanced ammonia buffering, which delays the onset of fatigue during high-intensity efforts. Unlike many studies that focus on acute “pre-workout” effects, this trial highlights the benefits of chronic, long-term loading to maintain elevated nitric oxide pools in skeletal muscle.
Actionable Insights
For those seeking to optimize performance and cardiovascular health, the study provides a specific, reproducible protocol. The effective daily dose was 3 grams of L-citrulline combined with 2.1 grams of beetroot extract (standardized to 300 mg of nitrates ). Crucially, this was not an acute dose taken once before exercise; it was administered daily for 9 weeks , divided into three doses at breakfast, lunch, and dinner.
This chronic approach suggests that longevity-focused individuals can benefit from maintaining high nitric oxide bioavailability, which supports vascular health and mitochondrial function. While triathletes were the test subjects, the underlying mechanisms—reduced ATP cost of exercise and improved oxygen uptake kinetics—are relevant for any adult aiming to maintain high-intensity functional capacity as they age. To maximize results, the L-citrulline should be pure (rather than citrulline malate, which would require a higher dose to achieve 3g of pure citrulline), and the beetroot extract must be standardized for nitrate content to ensure potency.
Context
- Institutions: University of Leon, University of Valladolid, University of the Basque Country, and University of Burgos.
- Country: Spain.
- Journal Name: Nutrients.
- Impact Evaluation: The impact score (JIF) of this journal is approximately 5.9 to 6.7 (based on 2022-2023 data), evaluated against a typical high-end range of 0–60+ for top general science; therefore, this is a High impact journal in the field of nutrition and dietetics.