Dr. Avik Roy is the chief scientific officer and chief of neurobiology at the Simmaron Research Institute, a nonprofit organization researching ways to treat patients with ME/CFS or Long Covid. In 2022, Dr. Roy won a Solve Ramsay Research Grant to develop new models for studying ME/CFS. Dr. Roy and his team have now published a paper in the Journal of Central Nervous System Disease that explains why some patients with ME/CFS experience orthostatic imbalance (sharply decreased blood pressure when they stand), which can cause dizziness, lightheadedness, or even fainting. Characteristically, Dr. Roy’s inventive team created an interesting new experimental model for this study, which they used to dissect the metabolic missteps responsible for this effect.
Earlier, Dr. Roy’s team found that patients with ME/CFS who experience orthostatic imbalance have too much tetrahydrobiopterin in their blood. Tetrahydrobiopterin is a cofactor (a molecule that enzymes need to do their work) for several important enzymes. Especially relevant for orthostatic imbalance is that tetrahydrobiopterin is a cofactor enzyme that makes nitric oxide. Because nitric oxide widens blood vessels to control blood pressure, it makes sense that high tetrahydrobiopterin reduces blood pressure. In this study, Dr. Roy’s team traced the origin of low blood pressure and orthostatic imbalance in patients with ME/CFS by dissecting the metabolic pathway responsible for making tetrahydrobiopterin—the pentose phosphate pathway.
In the pentose phosphate pathway, a six-carbon sugar (glucose) is broken down into a five-carbon sugar (ribose 5-phosphate; hence the name, pentose) and NADPH. Like tetrahydrobiopterin, NADPH is a critical cofactor; for example, one of NADPH’s important jobs is to protect against dangerous oxygen species, like free radicals. If cells need lots of NADPH (for example, if oxygen levels are high), then the cells can recycle the five-carbon sugar back into the six-carbon one to keep making NADPH. But if cells need little NADPH (for example, if oxygen levels are low), then they can instead use the five-carbon sugar to make other important molecules, like tetrahydrobiopterin.
Dr. Roy’s team found that the pentose phosphate pathway was more active in patients than it was in healthy participants, and the levels of other enzymes needed to convert the five-carbon sugar into tetrahydrobiopterin were higher as well. Patients with ME/CFS often have respiratory problems that lower oxygen levels in tissues, explaining why the pentose phosphate pathway produced more tetrahydrobiopterin (instead of NADPH) in these patients.
Dr. Roy’s team then devised an artificial system to study tetrahydrobiopterin production. They grew human cells under conditions that favored making tetrahydrobiopterin—with low levels of oxygen and high levels of the five-carbon sugar. Cells grown with low oxygen made more tetrahydrobiopterin than did cells grown with normal oxygen. But by experimentally inactivating an enzyme needed to make tetrahydrobiopterin (transaldolase, whose levels are also unusually high in patients with ME/CFS and orthostatic imbalance), the team reversed this effect, showing that they could experimentally control tetrahydrobiopterin production (and perhaps hinting at a way to treat patients).
The team compared plasma samples from patients with ME/CFS and orthostatic imbalance with those from healthy participants. Levels of tetrahydrobiopterin in patients’ samples were significantly higher than those in healthy participants’ samples. Adding patients’ plasma caused the cells to produce nitric oxide; but adding plasma from healthy participants did not. The more tetrahydrobiopterin in the plasma, the more nitric oxide the cells made.
Dr. Roy’s team believes the low oxygen levels in patients with ME/CFS stimulates the pentose phosphate pathway to make more tetrahydrobiopterin and nitric oxide, thus lowering blood pressure and promoting orthostatic imbalance. Increasing oxygen levels, perhaps by improving pulmonary function, might lower orthostatic imbalance for patients with ME/CFS. And since Dr. Roy’s team could lower tetrahydrobiopterin and nitric oxide levels by inactivating transaldolase, treatments that normalize transaldolase levels might also help.
Dr. Roy’s team will next use high-resolution methods to measure tetrahydrobiopterin production in patients more comprehensively. They will also include more patients to better detect how metabolism of patients with ME/CFS and orthostatic imbalance differs from that of healthy participants.
