How citrulline keeps muscles strong during physiological stress

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    How citrulline keeps muscles strong during physiological stress

    How citrulline keeps muscles strong during physiological stress

    According to previously published studies, supplementation with citrulline may be an interesting option if you want to retain or build muscle mass if you consume few calories or if there are few proteins in your diet. Researchers at Inserm in France studied the effect of citrulline on muscle cells - and discovered why.

    The researchers put muscle cells in test tubes, and mimicked the conditions that you find under normal conditions [Ctrl], in people with a low protein diet [AA/serum-] and in people with a low protein diet who supplement with supplement with L-citrulline [AA/serum + Cit].

    The researchers then looked at the amount of energy [actually: ATP] that the muscle cells invested in a number of processes, one of which was the production of muscle protein. They discovered that as the supply of amino acids diminishes, the muscle cell primarily reduces the synthesis of muscle protein. Citrulline supplementation, however, put an end to this cellular austerity measure.

    The researchers also simulated the effects of an muscular energy deficit in their test tubes. In organisms these effects occur for example as a result of a low-calorie diet or extreme exertion - and as a consequence of the use of the downright dangerous killer drug DNP.

    DNP sabotages the conversion of energy from nutrients into energy phosphate in the cells, and forces cells to release that energy as heat instead. As a result, cells must continuously convert nutrients into energy, and the energy consumption of the body increases drastically.

    Under standard conditions, the amino acid leucine was the best booster of muscle protein synthesis, the researchers found. But under energy stress caused by DNP, citrulline provided the most powerful anabolic or anti-catabolic stimulus.

    Mechanism
    "The consensus view that amino acid availability is the major limiting step in protein synthesis has prompted the idea that citrulline may stimulate protein synthesis after protein/energy deficiency by acting as a nitrogen source", write the researchers. "However, this hypothesis can be ruled out, because ARG (arginine) did not stimulate protein synthesis in the relevant incubation condition."

    "This work adds decisive evidence to the earlier ideas of a hierarchical arrangement of ATP-consuming processes [Biochem J. 1995 Nov 15;312(Pt1):163-7.] with protein synthesis being very sensitive to a decrease in ATP/ADP ratio. While many of these bioenergetic effects can be explained today by signalling pathways like those linked to AMPK, the effects of citrulline that we observed were not accompanied by any change in ATP/ADP ratio, respiration, or AMPK activation."

    "We propose that it is the hierarchy of ATP allocation to different ATP-consuming processes that is altered, for example, by a decrease in the activation energy of one or several enzymatic step(s) involved in or controlling protein synthesis."

    Source: Cachexia Sarcopenia Muscle. 2019 Aug;10(4):919-28.
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    Has anybody used this alone - or in their stack ? If so -results ? and at what dose ? Thanks

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    Nitric Oxide Supplements Reviewed: L-Citrulline, Agmatine and AAKG

    Posted by Nootropics Depot on 7th Mar 2018What does Nitric Oxide do for the body?

    Nitric oxide is a very interesting neurotransmitter within the body that mainly functions as a blood flow optimizer. What sets it apart from most of the neurotransmitters in our body is that it is a gas. This gives it a few distinct advantages, such as being able to diffuse through membranes rapidly, but it also has a few unique traits, such as a very short duration of action. The main purpose of nitric oxide in the body is to relax blood vessels, allowing for increased blood flow, which promotes blood flow through the body while also increasing blood flow to the brain. This makes nitric oxide boosters very popular among athletes. By promoting better blood supply to the muscles, we can ensure that things like lactic acid are moved out of the muscle, and that various nutrients are moved into the muscle. This will allow for slight gains in strength acutely, but more importantly, it will lead to increases in muscle recovery. In addition to this, extra blood flow can be quite the confidence booster, as it will make the muscles look much bigger post-exercise due to ‘the pump’ which is something Arnold Schwarzenegger made very popular in the documentary "pumping iron." Due to this, nitric oxide supplements are also often referred to as muscle pump supplements.
    Nitric oxide function goes far beyond helping enhance ‘the pump’, as it serves many other purposes throughout the body and even throughout the brain. The most obvious benefit, again has to do with blood supply. By relaxing blood vessels, nitric oxide can also help promote healthy blood pressure. Nitric oxide, by working on nitric oxide neurons, can also relax other smooth muscles; which can support digestive health.




    https://nootropicsdepot.com/articles...tine-and-aakg/

    - - - Updated - - -

    How Does Nitric Oxide Affect the Immune System?

    Nitric oxide is also a major supporter of the immune system and plays an intricate role in the bodies inflammatory response. The phagocytes in our body are armed with large quantities of nitric oxide and upon activation, the phagocytes release the nitric oxide onto bacteria. The nitric oxide in this case, is released into an environment that is highly saturated with the oxidant superoxide. Nitric oxide interacts with super oxide to create the strong oxidant peroxynitrite which kills the bacteria. In fact, in recent decades nitric oxide has been recognized as one of the most versatile players in the immune system. Nitric oxide is produced by three different NO synthases (NOS), the principal enzyme involved is the inducible type-2 isoform of nitric oxide synthase (NOS-2).
    How Does Nitric Oxide Affect the Brain?

    Within the brain, nitric oxide regulates blood flow (just like in the body). Beyond this, it interacts with the glutamate system, and thereby plays a major role in memory and learning. By interacting with glutamate systems, it can also cause excitotoxicity when it becomes dysregulated. So, it is no surprise that nitric oxide is strictly regulated. In fact, the excitatory amino acid glutamate, the most abundant CNS neurotransmitter, is an initiator of the reaction that forms nitric oxide. Nitric oxide binds to guanylyl cyclase, the cyclic guanosine-monophosphate (cGMP)-producing enzyme which is a soluble NO receptor, and through cGMP-mediated signaling cascades it expresses its modulating effects either as a post- or a pre-synaptic retrograde messenger. This is how nitric oxide can act as an excitatory neurotransmitter. However, it also acts on inhibitory gamma-aminobutyric acid (GABA)-ergic synaptic transmission. As such, nitric oxide can fill the role of an excitatory or inhibitory neurotransmitter in the brain.
    What are the Three Forms of Nitric Oxide Synthase?

    The regulation of nitric oxide is managed by three different enzymes, called the nitric oxide synthases. The three forms are inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). The phagocytes that we talked about earlier, mainly express iNOS which is capable of producing and releasing large bursts of nitric oxide, which may support immune response, but can also be counterproductive when there is no direct immune threat. Within the nervous system, nNOS is widely expressed and is responsible for producing nitric oxide in neurons. This leads to enhanced neuroplasticity, central regulation of blood pressure and relaxation of smooth muscle cells. Finally, eNOS is the most commonly expressed form of NOS and is expressed widely in blood vessels. Usually, when we think about enhancing nitric oxide function, we are focusing on eNOS as it produces vasodilation without many other effects.

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    I Want to Enhance Nitric Oxide Function, What Supplement Do I Use?

    The easiest route to support nitric oxide function is to increase the amount of substrate available for NOS to produce nitric oxide. The reaction that takes place in NOS to produce nitric oxide is as follows:
    2 L-Arginine + 3 NADPH + 3 H+ + 4 O2 ⇌ 2 L-Citrulline + 2 nitric oxide + 4 H 2O + 3 NADP+Nitric Oxide Synthase
    As you can see, the main substrate is L-Arginine, so we will want to increase the amount of L-Arginine available to NOS. There is one issue with this, and that is that L-Arginine has poor bioavailability; so it is actually fairly hard to get a meaningful increase in L-Arginine plasma levels by just simply consuming L-Arginine. Luckily for us, L-Arginine is one of three amino acids that play a role in the urea cycle; a cycle which converts toxic ammonia into the relatively non-toxic urea. The other two amino acids that play a key role in the urea cycle are L-Ornithine and L-Citrulline. The basis of the urea cycle, is that ammonia is converted to carbamoyl phosphate which then enters the urea cycle. The carbamoyl phosphate is then converted to L-Citrulline, which then converts to an intermediary molecule called arginosuccinate before converting to L-Arginine. The L-Arginine is then converted to urea and L-Ornithine.
    Urea Cycle Diagram
    Consider an L-Citrulline Supplement

    By supplementing with the highly bioavailable citrulline malate we can provide the urea cycle with excess L-Citrulline which will get converted to L-Arginine. This leads to a significant rise in plasma L-Arginine levels, which will then get converted by NOS to nitric oxide. Based on this, citrulline malate is currently the most highly regarded nitric oxide booster, as it leads to a very significant rise in nitric oxide. In addition to this, L-Citrulline speeds up the urea cycle which leads to more ammonia buffering.
    What about taking an Agmatine or AAKG Supplement?

    Besides supplementing with citrulline malate, there have also been efforts made to improve the bioavailability of L-Arginine. The first of which, is to complex the L-Arginine with Alpha Ketoglutarate, a molecule that is involved in the urea cycle. Theoretically this should increase the efficiency of L-Arginine as a nitric oxide booster, whilst also promoting healthy mitochondrial function. Anecdotally, arginine alpha ketoglutarate (AAKG) is a great nitric oxide booster, however, there is very little concrete scientific evidence for AAKG. The second way to increase L-Arginine bioavailability, is to decarboxylate it. Decarboxylated L-Arginine is known as agmatine, which goes a step further than just enhanced bioavailability, since agmatine functions as a neurotransmitter and actually does not act as a substrate for NOS. Instead agmatine turns NOS on and off. More specifically, it blocks iNOS and nNOS whilst promoting the activity of eNOS. This has several advantages, as over activation of iNOS and nNOS can lead to inflammation and the eNOS activity is preserved which produces the vasodilation we are after. Agmatine sulfate is a favorite among those seeking a "pump" as it appears to produce one of the strongest sensation of blood rushing into the muscle during exercise when compared to the other nitric oxide boosters.
    How to Choose the Best Nitric Oxide Supplement

    So which one do you choose? This really depends on your preferences at the end of the day, as all three are very efficacious nitric oxide boosters. If you would like to just take a small capsule and experience the vasodilatory effects, then agmatine sulfate is the best option. However, some people find that it has cognitive effects (mood boosting, calming and focus enhancement) that are not desirable in just a pure nitric oxide booster. If this is the case, then citrulline malate is a fantastic choice, as it will both be a very efficacious nitric oxide booster whilst also being an ammonia buffer which can stave off fatigue. The only issue with citrulline malate is that it is fairly sour and large doses of it need to be taken. In a homemade preworkout blend, it goes really well, by adding a sour tang that can cover up bitter flavors, especially when it is combined with one of our flavor packs. For those who would rather not deal with the sour flavor, an AAKG supplement is a great choice as it is completely tasteless. AAKG also has the potential added benefit of producing ATP by enhancing mitochondrial function. This is based on the fact that the alpha ketoglutarate in AAKG is used within mitochondria as an antioxidant and energy producer.
    Should I Stack L-Citrulline, Agmatine and AAKG?

    Various combination of all three can be used as well. By taking agmatine in combination with either AAKG or citrulline malate, we can potentially enhance the amount of nitric oxide that is produced via eNOS. This is based on the fact that agmatine diverts nitric oxide production away from iNOS and nNOS whilst enhancing nitric oxide output from eNOS, which at the end of the day we are after. Our recommendation would be to combine agmatine sulfate with citrulline malate. AAKG could also be combined with agmatine, however, we do not see much of a reason to combine both AAKG and citrulline malate as both simply enhance plasma arginine levels.

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