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Updated: Oct 28, 2025
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Published on: February 16, 2016
In vivo cardiopulmonary impact of skeletal M3Dq DREADD expression: a pilot study
Sandra G Vincent1, John T Fisher2
1Department of Biomedical and Molecular Sciences and Division of Respirology, Department of Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada. vincents@queensu.ca.
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).
Insights
Activation of designer receptors exclusively activated by designer drugs (DREADDs) in skeletal muscle significantly impacts cardiopulmonary function, reducing heart rate, activity, and ventilation. This suggests a link between skeletal muscle signaling and metabolic responses like torpor.
Area of Science:
- Physiology
- Pharmacology
- Cardiopulmonary Science
Background:
- The muscarinic M3 receptor (M3R) plays a role in cardiopulmonary control.
- Designer G-protein coupled receptors (DREADDs) in striated muscle have been linked to mortality and glucose metabolism.
- Previous studies suggest M3 DREADD activation impacts skeletal muscle and glucose metabolism.
Purpose of the Study:
- To investigate the impact of activating M3 DREADD selectively in skeletal muscle on cardiopulmonary function.
- To determine if M3 DREADD activation influences heart rate, body temperature, and locomotor activity.
- To explore potential links between skeletal muscle Gq signaling and metabolic responses.
Main Methods:
- Utilized M3 DREADD mice and wildtype controls, chronically instrumented for physiological measurements.
- Measured heart rate (HR), body temperature (Tb), and locomotor activity (ACT) in conscious mice.
- Administered clozapine N-oxide (CNO) to activate M3 DREADD and assessed physiological changes, including pulmonary ventilation and bronchoconstriction response.
Main Results:
- No significant differences in circadian HR, Tb, or ACT between M3 DREADD mice and controls.
- CNO administration significantly reduced HR, ACT, and pulmonary minute ventilation compared to baseline.
- M3 DREADD activation did not induce bronchoconstriction but was associated with cardiac arrhythmias, reduced Tb, HR, and ventilation.
Conclusions:
- Activation of M3 DREADD in skeletal muscle profoundly affects cardiopulmonary function.
- The observed reductions in HR, Tb, and ventilation suggest a mechanistic link between skeletal muscle Gq signaling and metabolic regulation.
- Findings may indicate a role for skeletal muscle signaling in the initiation of torpor-like states.
