Breathing with neuromuscular disease: Does compensatory plasticity in the motor drive to breathe offer a potential therapeutic target in muscular dystrophy?

Abstract

Duchenne muscular dystrophy is a fatal neuromuscular disease associated with respiratory-related morbidity and mortality. Herein, we review recent work by our group exploring deficits and compensation in the respiratory control network governing respiratory homeostasis in a pre-clinical model of DMD, the mdx mouse. Deficits at multiple sites of the network provide considerable challenges to respiratory control. However, our work has also revealed evidence of compensatory neuroplasticity in the motor drive to breathe enhancing diaphragm muscle activity during increased chemical drive. The finding may explain the preserved capacity for mdx mice to increase ventilation in response to chemoactivation. Given the profound dysfunction in the primary pump muscle of breathing, we argue that activation of accessory muscles of breathing may be especially important in mdx (and perhaps DMD). Notwithstanding the limitations resulting from respiratory muscle dysfunction, it may be possible to further leverage intrinsic physiological mechanisms serving to compensate for weak muscles in attempts to preserve or restore ventilatory capacity. We discuss current knowledge gaps and the need to better appreciate fundamental aspects of respiratory control in pre-clinical models so as to better inform intervention strategies in human DMD.

Keywords: Diaphragm; Duchenne muscular dystrophy; Electromyogram; Neuroplasticity; mdx mouse.