ME/CFS - possible disturbance to amino acid and nitrogen metabolism?

Production of nitric oxide (NO) - nitric oxide synthase (NOS)

In my previous post  Endothelial dysfunction in ME/CFS – and cytochrome CYP2C9, we learned from wikipedia, that endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium and/or increased inactivation of NO by reactive oxygen species.

We can learn more from wikipedia about the production of Nitric oxide (NO) and Nitric oxide synthase:

The endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow.

NO is produced by the three calcium/calmodulin controlled isoenzymes called nitric oxide synthases (NOS), all present in skeletal muscle, but named because of the tissues from where they were first purified (neuronal and endothelial), but all three types of NOS are expressed in the skeletal muscle:

• Neuronal NOS (nNOS) 
• Endothelial NOS (eNOS) 
• Inducible NOS (iNOS) - is mainly expressed during inflammatory responses

NOS generates NO upon the conversion of the amino acid L-arginine to L-citrulline and it is regulated by multiple mechanisms.

Arginine can also be converted to the amino acid ornithine:

arginine + O₂  →  citrulline + nitric oxide (NO)

arginine  → ornithine + urea

Further details and fine figures, please, read this article: Enzymes of Arginine Metabolism

What does the litterature have to say about the levels of these amino acids in ME/CFS patients?

Arginine, citrulline and ornithine in ME/CFS patients

From this article NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome we learn:

ME/CFS patients have reduced levels of glutamine and ornithine = possible disturbance to amino acid and nitrogen metabolism

"Identified metabolites that were found to be significantly altered between the groups were subjected to correlation analysis to potentially elucidate disturbed metabolic pathways. Our results showed a significant reduction of glutamine (P=0.002) and ornithine (P<0.05) in the blood of the CFS samples. Correlation analysis of glutamine and ornithine with other metabolites in the CFS sera showed relationships with glucogenic amino acids and metabolites that participate in the urea cycle. This indicates a possible disturbance to amino acid and nitrogen metabolism."

And from this article Levels of Nitric Oxide Synthase Product Citrulline Are Elevated in Sera of Chronic Fatigue Syndrome Patients:

ME/CFS patients have elevated levels of citrulline

"Serum levels of citrulline, a product of nitric oxide synthase activity, were measured in 36 CFS patients and 16 controls to determine whether synthase activity may be elevated in CFS patients. Serum citrulline levels were found to be significantly elevated in CFS patients and, in addition, there was a trend towards higher levels in CFS patients with stronger symptoms. These results provide support for the view that nitric oxide synthase activity tends to be elevated in CFS patients, thus supporting a prediction of the elevated nitric oxide/peroxynitrite theory of CFS etiology."

It would be reallye nice to have these results replicated in a new study - all parameters measured at the same time in the same study! And if someone follow this idea, please look at the NK cells too!

Because of this article Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome says:  "...These results demonstrate that the L-Arg-induced activation of NK activity is mediated by NO and that a possible dysfunction exists in the NO-mediated NK cell activation in CFS patients."

Further reading:
Nitric Oxide Synthase Pathway May Mediate Human Natural Killer Cell Cytotoxicity

Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency

Hematologic and Urinary Excretion Anomalies in Patients with ChronicFatigue Syndrome