According to a recent mouse study, the target is an ion channel that has been already shown to impact blood pressure in obese mice.
According to Johns Hopkins Medicine scientists, a recent study with obese mice adds to evidence that specialized channel proteins are potential therapeutic targets for sleep apnea and other unusually slow breathing disorders in obese individuals.
The protein, a cation channel known as TRPM7, is located in carotid bodies, minute sensory organs in the neck that sense changes in oxygen and carbon dioxide levels, as well as certain hormones such as leptin, in the bloodstream. TRPM7 proteins aid in the transport and regulation of positively charged molecules into and out of the cells of the carotid bodies.
Lenise Kim, Ph.D., a postdoctoral fellow at Johns Hopkins Medicine and the leader of the current study, expands on earlier results from the lab that indicated TRPM7 had a role in the development of high blood pressure in mice.
Linking TRPM7 to Breathing Disorders
The recent research, which was detailed in a study that was recently published in The Journal of Physiology, demonstrated that TRPM7 is involved in suppressing breathing in obese mice that exhibit symptoms of sleep-disordered breathing.
Up to 45% of obese Americans are thought to suffer from sleep-disordered breathing, which is characterized by breathing that stops and restarts while a person is asleep. Untreated, the condition can worsen the course of heart disease and diabetes, cause significant fatigue, and even death due to poor oxygenation. Weight loss and nightly use of continuous positive airway pressure devices, or CPAP, can help alleviate sleep apnea, however, CPAP treatment is often poorly tolerated by patients.
“CPAP actually works for most patients, the fact is that most patients are not adherent to this treatment,” says Kim. “So knowing that TRPM7 contributed to high blood pressure and sleep-disordered breathing, we wondered if blocking or eliminating that channel could offer a new treatment target.”
Blocking TRPM7 to Improve Ventilation
Using silencing RNA, the researchers knocked out the gene responsible for the production of the TRPM7 channel protein, reducing the number of TRPM7 channels in the carotid bodies of obese mice. Mice then underwent a sleep study, during which researchers observed their breathing patterns and blood oxygen levels.
In obese mice with blocked TRPM7, the researchers noted large differences in their rates of minute ventilation, or the amount of air inhaled and exhaled by the lungs per minute. The obese mice showed a 14% increase in their minute ventilation, 0.83 milliliters of air per minute (mL/min/g) during sleep. Researchers say these data are a significant improvement in ventilation when compared to obese mice that had TRPM7, whose average minute ventilation was 0.73 mL/min/g. These findings indicate the ventilatory capacity in these mice was improved while they slept, effectively combating the decreased breathing patterns of sleep apnea.
Notably, the researchers found that despite the increased ventilation in obese mice lacking TRPM7, their blood oxygen levels did not increase. For this finding, researchers exposed the mice to hypoxic — or low-oxygen — environments and then monitored their breathing patterns. Although the mice’s minute ventilation increased by 20%, from 1.5 mL/min/g to 1.8 mL/min/g, their bloodstream oxygen levels decreased, meaning their additional inhalations did not help saturate the body with more oxygen.
“This suggests that treatments designed to reduce or erase TRPM7 in carotid bodies would not be workable for people living in low-oxygen environments, such as those in very high altitudes, or for those with conditions that already limit blood oxygen saturation, such as lung disease,” says Kim.
Leptin and TRPM7: A Hormonal Connection
The team’s findings also illustrate that the hormone leptin — which is produced in fat cells and is responsible for curbing appetite — may cause an increase in TRPM7 channels. Leptin is already known to accelerate production and increase the concentration of TRPM7 in carotid bodies. In obese mice who possess more fat cells, the increased amount of leptin may lead to an oversaturation of TRPM7. These high levels of the cation channel in turn may lead to the low respiration rates observed in obese mice with TRPM7.
“We have shown that the genetic knockdown of TRPM7 in carotid bodies reduces suppressed respiration in sleep-disordered breathing,” says Vsevolod (Seva) Polotsky, M.D., Ph.D., director of sleep research and professor of medicine at the Johns Hopkins University School of Medicine. “While more research is needed, carotid body TRPM7 is a promising therapeutic target not only for hypertension in obesity but also for abnormal breathing during sleep associated with obesity.”
Reference: “TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies” by Lenise J. Kim, Mi-Kyung Shin, Huy Pho, Wan-Yee Tang, Nishitha Hosamane, Frederick Anokye-Danso, Rexford S. Ahima, James S. K. Sham, Luu V. Pham and Vsevolod Y. Polotsky, 10 October 2022, The Journal of Physiology.
DOI: 10.1113/JP283678
The study was funded by the National Heart, Lung, and Blood Institute, the American Academy of Sleep Medicine Foundation, the American Thoracic Society, and the American Heart Association (AHA).
The authors of this study report no conflict of interest.
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