Sleep Concept

Johns Hopkins researchers have identified a new potential treatment target for sleep apnea

sleep concept

Sleep apnea is a potentially dangerous sleep disorder in which breathing stops and restarts several times while you sleep.

According to a recent mouse study, the target is an ion channel that has already been shown to impact blood pressure in obese mice.

According to Johns Hopkins Medicine scientists, a recent study in obese mice adds to the evidence that specialized channel proteins are potential therapeutic targets for sleep apnea and other unusually slow breathing disorders in obese people.

The protein, a cation channel known as TRPM7, is located in the carotid bodies, tiny sensory organs in the neck that detect changes in oxygen and carbon dioxide levels, as well as certain hormones such as leptin, in the blood. TRPM7 proteins help transport and regulate positively charged molecules into and out of carotid body cells.

Lenise Kim, Ph.D., a postdoctoral fellow at Johns Hopkins Medicine and leader of the current study, expands on previous findings from the lab that indicated TRPM7 had a role in the development of high blood pressure in mice.

Recent research, which was detailed in a study recently published in The Journal of Physiologydemonstrated that TRPM7 is involved in the suppression of respiration in obese mice that show symptoms of sleep-disordered breathing.

It is believed that up to 45% of obese Americans suffer from sleep disordered breathing, which is characterized by breathing that stops and starts again while a person is sleeping. Untreated, the disease can worsen the course of heart disease and diabetes, cause significant fatigue and even death due to poor oxygenation. Weight loss and nighttime use of continuous positive airway pressure, or CPAP, devices can help relieve sleep apnea, however, CPAP treatment is often poorly tolerated by patients.

“CPAP actually works for most patients, the fact is most patients don’t adhere to this treatment,” says Kim. “So knowing that TRPM7 contributes to high blood pressure and sleep-disordered breathing, we wondered if blocking or eliminating this channel might offer a new treatment target.”

Use of silence

Ribonucleic acid (RNA) is a DNA-like polymeric molecule that is essential in various biological roles in gene coding, decoding, regulation and expression. Both are nucleic acids, but unlike DNA, RNA is single-stranded. A strand of RNA has a backbone made up of alternating sugar (ribose) and phosphate groups. Attached to each sugar is one of four bases: adenine (A), uracil (U), cytosine (C) or guanine (G). Different types of RNA exist in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA).

” data-gt-translate-attributes=”[{” attribute=””>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.

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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