In vivo cardiopulmonary impact of skeletal M3Dq DREADD expression: a pilot study

Abstract

The muscarinic M3 receptor (M3R) 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 M3Dq DREADD (Designer Receptor Exclusively Activated by Designer Drug), selectively expressed in skeletal muscle (SKM) impacts glucose metabolism. We investigated whether activation of SKM M3Dq impacts cardiopulmonary function. Heart rate (HR), body temperature (Tb) and locomotor activity (ACT) were measured in 4 conscious, chronically instrumented M3Dq DREADD mice and 4 wildtype controls. Circadian values of HR, BT and ACT were not different between genotypes (p > 0.05). Activation of the M3Dq 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). M3Dq 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).

Lung-innervating neurons expressingTmc3can induce broncho-constriction and dilation with direct consequences for the respiratory cycle

“…Next we sought to visualize and quantify the in vivo effects of Tmc3+ VG neuron inhibition or activation on lung function and bronchial integrity. Cre dependent Designer Receptor Exclusively Activated by Designer Drugs (DREADD) mice have been successfully utilized for chemogenetic neuronal control in a variety of in vivo studies, including efforts applying DREADD technology to understand breathing disorders or enable further insights into cardiopulmonary biology (31)(32)(33)(34)(35). This prompted us to generate inhibitory (hm4di, "DREADD-Gi") and activating (hm3dq, "DREADD-Gq") Tmc3-Cre-DREADD mice (Fig.…”