Obstructive sleep apnea (OSA) involves recurring obstruction of the upper airway during sleep due to loss of genioglossus (GG) muscle tone. OSA affects 54 million Americans and many more throughout the world leading to cardiovascular morbidity and mortality. The mainstream treatment with continuous positive airway pressure (CPAP) has only 50% adherence. Emergent pharmacotherapy does not cover all aspects of OSA, thus novel drug development for OSA is required. Previously, our lab has shown that diet-induced obese (DIO) mice develop OSA. Recently we found that the melanocortin 4 receptor (MC4R) agonist setmelanotide (SET) augments hypercapnic ventilatory response (HCVR) and improves OSA acting on MC4R neurons in the retrotrapezoid nucleus (RTN). Even though we have demonstrated that SET treats OSA in DIO mice, it is yet unknown if this is due to improvement in GG muscle activity during sleep. We hypothesized SET improves OSA by increasing GG muscle activity. For our study purpose, we head mounted 7 male C57BL/6J mice with EEG electrodes and EMG electrodes to the GG muscle. After recovery we performed sleep studies and GG activity recording in a randomized cross-over trial of SET (1 mg/kg) vs vehicle (Veh). Sleep studies were followed by HCVR (8% CO 2 challenge during quiet wakefulness). Baseline recording was done for 1 hour before SET or Veh administration. Quiet wakefulness at normocapnic conditions has been used to normalize GG activity during NREM or REM or HCVR (8% CO 2 ) following SET or Veh administration. SET administration significantly increased GG muscle activity during both non-rapid eye movement sleep (NREM) (SET: 0.86 ± 0.08 vs. Veh:0.48 ± 0.04; p < 0.005) and rapid eye movement sleep (REM) (SET: 0.38 ± 0.05 vs. Veh:0.27 ± 0.04; p < 0.05). Furthermore, SET significantly increases GG muscle activity during HCVR (SET: 2.04 ± 0.25 vs. Veh:1.25 ± 0.11; p < 0.05). Our study finding suggests SET improves OSA by improving GG muscle activity. In the future, we will look for the mechanism behind SET induced GG muscle activity improvement in DIO mice. We hypothesize that SET increases GG muscle activity and improves OSA by activating MC4R neurons in the RTN. We will test our hypothesis in DIO mice by utilizing state-of-the art chemogenetic (designer receptor exclusively activated by designer drugs, DREADD) and iCre/MC4R-flox based gene knockdown approach. Grant support: R01 HL174409 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Islam et al. (Fri,) studied this question.