0068 Role of Melanocortin 4 Receptor Signaling in Sleep-Disordered Breathing

Abstract Introduction Obstructive sleep apnea (OSA) affects many people throughout the world and is a leading cause of cardiovascular morbidity and mortality. One of the major causes of OSA is loss of genioglossus (GG) muscle tone during sleep. Emergent pharmacotherapy has limitations and new drugs with better potential to treat OSA are required. We have previously shown that diet-induced obese (DIO) mice develop OSA and melanocortin 4 receptor (MC4R) agonist setmelanotide (SET) could be used for OSA treatment. We have also shown MC4R agonists act in the retrotrapezoid nucleus (RTN) to augment hypercapnic ventilatory response (HCVR). We hypothesized that SET treats OSA by increasing GG muscle tone and that effects of setmelanotide on sleep and breathing can be localized to the MC4R on the RTN neurons. Methods We transfected DIO MC4R-Cre mice with adeno-associated virus (AAV) harboring excitatory designer receptor exclusive activated by designer drugs (DREADD) and DIO MC4R-flox mice with AAV-Cre-recombinase (icre) into the RTN. Transgenic and C57BL/6J mice were headmounted with EEG and GG and nuchal EMG electrodes. Sleep and HCVR studies (8% CO2 challenge) were performed in the plethysmography chamber. Results SET (1 mg/kg, i.p) significantly increased GG muscle activity during NREM sleep (SET: 0.86 ± 0.08 vs. Veh: 0.48 ± 0.04 a.u.; p 0.005), REM sleep (SET: 0.38 ± 0.05 vs. Veh: 0.27 ± 0.04 a.u.; p 0.05) and during HCVR (SET: 2.04 ± 0.25 vs. Veh: 1.25 ± 0.11 a.u.; p 0.05). Experiments in MC4R-Cre mice showed that RTN-MC4R neurons activation by DREADD ligands increased sleep efficiency (Veh: 49.69 ± 0.02% vs. J60: 58.07 ± 0.03% of the light phase). Experiments in MC4R-flox mice showed that MC4R knockdown in RTN abolished effects of SET on HCVR (control, SET: 0.29 ± 0.02 vs. Veh: 0.25 ± 0.03; p 0.05; MC4R knockdown, SET: 0.17 ± 0.03 vs. Veh: 0.19 ± 0.04; p 0.05). Conclusion Our study suggests SET targets RTN-MC4R neurons to augment HCVR and treats OSA by improving GG muscle activity. Furthermore, RTN-MC4R neurons activation can increase total sleep time. Support (if any) R01 HL174409