In vivo cardiopulmonary impact of skeletal M(3)Dq DREADD expression: a pilot study

The muscarinic M(3) receptor (M(3)R) is implicated in cardiopulmonary control and many other peripheral physiologic functions. Previous observations report mortality in mice expressing a Gq-linked designer G-protein coupled receptor (Dq) selectively in striated muscle, while M(3)Dq DREADD (Designer Receptor Exclusively Activated by Designer Drug), selectively expressed in skeletal muscle (SKM) impacts glucose metabolism. We investigated whether activation of SKM M(3)Dq impacts cardiopulmonary function. Heart rate (HR), body temperature (Tb) and locomotor activity (ACT) were measured in 4 conscious, chronically instrumented M(3)Dq DREADD mice and 4 wildtype controls. Circadian values of HR, BT and ACT were not different between genotypes (p > 0.05). Activation of the M(3)Dq DREADD by clozapine N-oxide (CNO; 0.1 mg/kg) resulted in: a significant drop in heart rate, 2 h after injection, compared with a time-matched baseline control period from the same animals (460 ± 28 vs. 532 ± 6, p < 0.05), significantly lower ACT compared to the baseline control (p < 0.05) and reduced pulmonary minute ventilation compared to pre-CNO control (p < 0.05). M(3)Dq DREADD activation did not cause bronchoconstriction (separate protocol), however, there was a concomitant reduction in HR, Tb and ventilation, accompanied by cardiac arrhythmias. We speculate that reductions in Tb, HR and ventilation reflect a mechanistic link between SKM Gq signaling and the metabolic responses associated with the initiation of torpor. Supported by the Canadian Institutes of Health Research (CIHR MOP-81211).