Lung Loss of MECP2 Linked to Breathing Problems in Mouse Study
The loss of MECP2 protein — defective in most cases of Rett syndrome — in the lungs may result in breathing problems, according to a mouse study.
The findings suggest that this may due to altered amounts of fats in the lungs, and could have important implications for treating patients.
The researchers found that the use of statins, a type of cholesterol-lowering medication, eased respiratory symptoms and lowered blood levels of fats.
“These data implicate autonomous pulmonary [lung-related] loss of MECP2 in respiratory symptoms for the first time and have immediate impacts on patient care,” the team wrote.
The study, “Aberrant lung lipids cause respiratory impairment in a Mecp2-deficient mouse model of Rett syndrome,” was published in the journal Human Molecular Genetics.
Rett syndrome is most often caused by a mutation in MECP2, a gene that provides instructions to make the MECP2 protein. Until now, research has mainly focused on the role of the MECP2 gene in the central nervous system — the brain and spinal cord — and respiratory symptoms such as breathing problems have been linked to impaired neuronal or nerve cell function.
However, the lungs are rich in MECP2, and researchers in Canada thought the protein must play an important role there. In fact, the lung is a major site of fatty acid production (de novo lipogenesis), which made the scientists hypothesize that lung lipid (fat) metabolism may be a target of MECP2-driven gene activity regulation. Notably, altered pulmonary lipid metabolism has been reported in several respiratory diseases.
To explore this idea, the researchers used mice with a deletion of Mecp2, which is the mouse form of MECP2. Typically, male mice in this model show a rapid decline of health and die in early adulthood; female mice develop neurological symptoms and have a longer lifespan.
In their first set of experiments, the scientists found that a lack of MECP2 protein resulted in an abnormal accumulation of lipids, including cholesterol, in the lungs. When the investigators looked more closely at certain components that make up lung surfactant — a mixture of lipids and proteins that reduces the surface tension inside the lungs, facilitating normal gas exchange — they found that the amount of phospholipids (a type of fat molecule) was reduced. Such a reduction could affect the lung’s ability to exchange gases efficiently, creating breathing problems, the scientists said.
To understand whether these changes could be a result of MECP2 deficiency in the lungs, the researchers used mice carrying a mutant Mecp2 gene — but this time, only in lung cells responsible for synthesizing, secreting, and recycling pulmonary surfactant.
The results showed that this specific lack of MECP2 was enough to cause the accumulation of triglycerides, a type of lipid, in the lungs. While these mice did not show any neurological symptoms, they had an increased number of apnea or breath-holding episodes — a characteristic respiratory symptom of Rett.
A similar increase in apnea episodes was found in animals with a specific Mecp2 deletion in neurons of the hindbrain, a brain region that controls breathing and other functions.
Both lung-specific and hindbrain-specific MECP2 deletion mice showed elevated breathing frequency, but only those with a targeted deletion in the hindbrain had an increase in tidal volume — the amount of air that moves in or out of the lungs with each respiratory cycle.
Due to these findings, the researchers thought that a lack of MECP2 might lead to respiratory symptoms via two local, autonomous mechanisms.
“The combined loss of MECP2 from both centers likely imparts the full spectrum of respiratory symptoms in RTT [Rett],” the investigators wrote.
As the abnormal accumulation of lipids appeared to contribute to the respiratory symptoms seen in the mutant mice, the researchers thought of using a lipid-lowering medication called fluvastatin. As a statin, fluvastatin works by lowering the blood levels of cholesterol and triglycerides by blocking an enzyme called HMG-CoA-reductase. Fluvastatin has been associated with improved overall health, motor activity, and metabolism in mice with a Mecp2 mutation.
Weekly treatment with fluvastatin lowered the levels of circulating lipids, but in the lungs, only the levels of triglycerides were reduced. Besides having an effect on the levels of lipids, fluvastatin also improved health scores, motor coordination, and breathing frequency.
“Therefore, statin treatment can lower lung lipids and improve respiratory symptoms in mouse models of [Rett],” the researchers wrote.
Altogether, “these findings provide mechanistic evidence for the respiratory defects in [Rett syndrome] and have important translational value for patients,” the team concluded.