Respiratory performance in Duchenne muscular dystrophy: Clinical manifestations and lessons from animal models

Abstract

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials.

Keywords: D2.mdx mice; Duchenne muscular dystrophy; control of breathing; mdx mice; peak inspiratory pressure.

FIGURE 1

Schematic diagram of the dystrophin–glycoprotein complex situated at the sarcolemma. Dystrophin binds to the actin cytoskeleton via the N‐terminus. The sarcospan–sarcoglycan sub‐complex forms part of the dystrophin–glycoprotein complex. Syntrophins are adaptor proteins that link dystrophin with signalling molecules. α‐Dystroglycan is a laminin‐binding protein that binds to the transmembrane protein, β‐dystroglycan. Dystrophin is a microtubule‐associated protein. Created with BioRender.com.

FIGURE 2

Main features of Duchenne muscular dystrophy that contribute to respiratory system morbidity. Created with BioRender.com.

FIGURE 3

Characteristics of the mdx mouse model of Duchenne muscular dystrophy. Created with BioRender.com.

FIGURE 4

Characteristics of the mdx utrn ^−/− and mdx utrn ^+/− mouse models of Duchenne muscular dystrophy. Created with BioRender.com.

FIGURE 5

Characteristics of the golden retriever muscular dystrophy (GRMD) canine model of Duchenne muscular dystrophy. Created with BioRender.com.

FIGURE 6

Characteristics of D2.mdx mouse model of Duchenne muscular dystrophy. Created with BioRender.com.