The study identified potential new therapeutic targets for sleep apnea

In a new study of obese mice, researchers at the Johns Hopkins School of Medicine say they have added new evidence that special channel proteins may be therapeutic targets for sleep apnea and similar abnormally slow breathing disorders in obese people
.

The protein, a cation channel called TRPM7, is found in the carotid artery body, a tiny sensory organ in the neck that detects changes in oxygen and carbon dioxide in the blood, as well as certain hormones
like leptin.
The TRPM7 protein helps transport and regulate the flow of positively charged molecules in and out of carotid somatic cells
.

The new study, conducted at the Johns Hopkins Medical Polotsky Research Laboratory and led by postdoc Dr.
Lenise Kim, builds on previous findings from the lab that showed TRPM7 promotes the development of
high blood pressure in mice.

A report published Oct.
10 in The Journal of Physiology describes the latest experiments that reveal that TRPM7 plays a respiration-inhibiting role
in obese mice with symptoms of sleep-disordered breathing.

Sleep-disordered breathing is characterized by intermittent breathing during sleep, and it is estimated that up to 45 percent of obese people in the United States are affected
by it.
If left untreated, this condition can worsen the progression of heart disease and diabetes, leading to severe fatigue, and death
due to insufficient oxygenation.
Lifestyle changes, such as weight loss and nighttime use of a continuous positive airway pressure device (CPAP), can relieve sleep apnea, but CPAP treatment is often difficult to tolerate
.

"CPAP actually works for most patients, and the truth is that most patients don't stick to this treatment," Kim said
.
"Therefore, knowing that TRPM7 causes hypertension and sleep-disordered breathing, we wanted to know if blocking or eliminating this channel could provide a new therapeutic target
.
"

Using silencing RNA, the researchers knocked out the gene responsible for the production of TRPM7 channel proteins, reducing the number of TRPM7 channels in the carotid artery bodies of
obese mice.
The researchers then conducted sleep studies on the mice, during which the researchers observed their breathing patterns and blood oxygen levels
.

In obese mice with TRPM7 blockage, the researchers noticed large differences
in their minute ventilation rate (i.
e.
, the amount of air inhaled and exhaled from the lungs per minute).
Obese mice had a 14% increase in ventilation per minute during sleep, 0.
83 milliliters per minute (mL/min/g).

The researchers said these data showed significant improvements in ventilation compared to obese mice containing TRPM7, which had an average minute ventilation of 0.
73 mL/min/g
.
These findings suggest that the breathing capacity of these mice improved during sleep, effectively overcoming the decline
in breathing patterns of sleep apnea.

Notably, the researchers found that although obese mice lacking TRPM7 had increased breathing, they did not have increased
blood oxygen levels.
To make this discovery, the researchers exposed mice to hypoxia or hypoxia and then monitored their breathing patterns
.
Although the mice had a 20 percent increase in minute ventilation, from 1.
5 mL/min/g to 1.
8 mL/min/g, their blood oxygen levels decreased, meaning their extra inhalation did not help fill the body with more oxygen
.

"This suggests that treatments aimed at reducing or eliminating TRPM7 in carotid artery tissue are not suitable for people living in low-oxygen environments, such as those living at high altitudes, or people who have already restricted blood oxygen saturations, such as those with lung disease," Kim said
.

The team's findings also suggest that the hormone leptin, produced by fat cells and responsible for suppressing appetite, may lead to an increase in
TRPM7 channels.
We already know that leptin can accelerate the production of TRPM7 in the carotid artery body and increase its concentration
.
In obese mice with more fat cells, an increase in the amount of leptin may lead to supersaturation of TRPM7
.
These high levels of cation channels may in turn lead to the low respiratory rates
observed in obese mice containing TRPM7.

Vsevolod (Seva), MD, director of sleep research at Johns Hopkins University School of Medicine, said, "We have shown that gene suppression of TRPM7 in the carotid body can reduce respiratory depression in sleep-disordered breathing
.
" "While more research is needed, carotid body TRPM7 is a promising therapeutic target not only for hypertension in obesity, but also for obesity-related sleep breathing abnormalities
.
"

Other researchers involved in the study include 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, and Wan-Yee Tang
of the University of Pittsburgh.

This research was supported
by NIH R01 HL128970, R01 HL133100 and R01 HL12892 grants, the American Academy of Sleep Medicine 238-BS-20 Fund, the American Thoracic Society Unrestricted Award, the American Heart Association (AHA) Postdoctoral Fellowship Award 828142, and the AHA Career Development Award 19CDA34700025.

Journal Reference:

1. 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, Vsevolod Y.
   Polotsky.
   TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies.
   The Journal of Physiology, 2022; DOI: 10.
   1113/JP283678