Researchers from Johns Hopkins Medicine say that their study with obese mice has added to the evidence that certain channel proteins could be used to sleep apnea treatment and other problems with breathing that are unusually slow in obese people.
The carotid bodies, which are tiny sensory organs in the neck that sense changes in oxygen and carbon dioxide as well as some blood-borne hormones like leptin, include the protein, a cation channel known as TRPM7. TRPM7 proteins control and move positively charged molecules into and out of the cells of the carotid bodies.
The new study, which was led by Lenise Kim, Ph.D., a postdoctoral fellow at Johns Hopkins Medicine, builds on earlier lab findings that showed TRPM7 played a role in mice getting high blood pressure.
The most recent research, which was described in a paper that came out on October 10 in The Journal of Physiology, showed that TRPM7 is involved in making it hard for obese mice with sleep disordered breathing to breathe.
Up to 45% of obese Americans are thought to experience sleep disordered breathing, which is defined by breathing that comes and goes throughout sleep. If left untreated, the illness can exacerbate diabetes and heart disease, lead to severe exhaustion, and even result in death from inadequate oxygenation. Even though patients don’t always like CPAP therapy, lifestyle changes like losing weight and using CPAP machines regularly can help sleep apnea treatment.
The problem is that most patients don’t stick to this sleep apnea treatment, despite the fact that CPAP genuinely works for the majority of patients, claims Kim. Since TRPM7 was a factor in both high blood pressure and sleep apnea, researchers thought about whether blocking or shutting down that channel could be a new therapeutic target.
The number of TRPM7 channels in the carotid bodies of obese mice was decreased by the researchers’ use of silencing RNA to disrupt the gene producing the TRPM7 channel protein. Then, during a sleep study on mice, scientists monitored their blood oxygen levels and breathing patterns.
The amounts of air breathed and expelled by the lungs per minute, or minute ventilation rates, were significantly different in obese mice with inhibited TRPM7. The minute ventilation of the obese mice increased by 14% as they slept, reaching 0.83 milliliters of air per minute per kilogram (mL/min/g). When compared to obese mice with TRPM7, whose average minute ventilation was 0.73 mL/min/g, researchers claim that these data show a considerable improvement in ventilation. These results show that these mice were able to breathe better while they slept, reversing the fact that they breathed less when they had sleep apnea.
Notably, the researchers discovered that even while fat mice lacking TRPM7 had higher breathing rates, their blood oxygen levels did not rise. Researchers subjected the mice to hypoxic, or low-oxygen, conditions and then observed the mice’s breathing habits to arrive at this conclusion. The mice’s bloodstream oxygen levels declined even though their minute ventilation increased by 20%, from 1.5 mL/min/g to 1.8 mL/min/g, indicating that their greater inhalations did not help saturate the body with more oxygen.
This suggests that therapies intended to decrease or eliminate TRPM7 in carotid bodies would not be effective for people who reside in low-oxygen environments, like those who are at extremely high altitudes, or for those who already have conditions that lower blood oxygen saturation, like lung disease, says Kim.
The research team’s findings also show how the hormone leptin, which is made in fat cells and is in charge of reducing appetite, may result in an increase in TRPM7 channels. TRPM7 levels and production are already known to be accelerated by leptin in carotid bodies. Leptin levels may rise in obese mice because they have more fat cells, which could cause TRPM7 to become overstimulated. The decreased respiration rates seen in obese mice with TRPM7 may, in turn, be a result of these high cation channel concentrations.
According to Vsevolod (Seva) Polotsky, M.D., Ph.D., director of sleep research and professor of medicine at the Johns Hopkins University School of Medicine, “We have demonstrated that genetic knockdown of TRPM7 in carotid bodies decreases repressed respiration in sleep-disordered breathing.” Even though more research needs to be done, carotid body TRPM7 is a possible therapeutic target for both sleep apnea caused by obesity and high blood pressure in obese people.
Mi-Kyung Shin, Huy Pho, Nishitha Hosamane, Frederick Anokye-Danso, Rexford Ahima, James Sham, and Luu Pham of the Johns Hopkins University School of Medicine, as well as Wan-Yee Tang of the University of Pittsburgh, are other researchers who have contributed to this study.
The American Academy of Sleep Medicine Foundation 238-BS-20, the American Thoracic Society Unrestricted Award, the American Heart Association (AHA) Postdoctoral Fellowship Award 828142, and the AHA Career Development Award 19CDA34700025 all provided funding for this study. NIH R01 HL128970, R01 HL133100, and R01 HL12892 grants were also provided by the National Heart, Lung, and Blood Institute.
