Non-Invasive Optical Motion Tracking Allows Monitoring of Respiratory Dynamics in Dystrophin-Deficient Mice.

Angelika Svetlove,Christian Dullin,Marietta Andrea Markus,Frauke Alves,Swen Hülsmann,Jonas Albers,Jana Zschüntzsch

doi:10.3390/cells11050918

Abstract

Duchenne muscular dystrophy (DMD) is the most common x-chromosomal inherited dystrophinopathy which leads to progressive muscle weakness and a premature death due to cardiorespiratory dysfunction. The mdx mouse lacks functional dystrophin protein and has a comparatively human-like diaphragm phenotype. To date, diaphragm function can only be inadequately mapped in preclinical studies and a simple reliable translatable method of tracking the severity of the disease still lacks. We aimed to establish a sensitive, reliable, harmless and easy way to assess the effects of respiratory muscle weakness and subsequent irregularity in breathing pattern. Optical respiratory dynamics tracking (ORDT) was developed utilising a camera to track the movement of paper markers placed on the thoracic-abdominal region of the mouse. ORDT successfully distinguished diseased mdx phenotype from healthy controls by measuring significantly higher expiration constants (k) in mdx mice compared to wildtype (wt), which were also observed in the established X-ray based lung function (XLF). In contrast to XLF, with ORDT we were able to distinguish distinct fast and slow expiratory phases. In mdx mice, a larger part of the expiratory marker displacement was achieved in this initial fast phase as compared to wt mice. This phenomenon could not be observed in the XLF measurements. We further validated the simplicity and reliability of our approach by demonstrating that it can be performed using free-hand smartphone acquisition. We conclude that ORDT has a great preclinical potential to monitor DMD and other neuromuscular diseases based on changes in the breathing patterns with the future possibility to track therapy response.

Highlights

Duchenne muscular dystrophy (DMD) is the most prevalent and one of the most serious muscular dystrophies [1] for which no curative treatment is yet available [2,3]
We developed a novel, simple, low cost and non-invasive approach to track respiratory dynamics based on optical imaging utilising a camera and markers placed on the thoracic-abdominal region in the mdx mouse model of Duchenne muscular dystrophy
Optical Respiratory Dynamics Tracking (ORDT) was for the first time applied to successfully differentiate breathing behaviour of diseased mdx mice from healthy controls

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most prevalent and one of the most serious muscular dystrophies [1] for which no curative treatment is yet available [2,3]. The cause of DMD is a deletion or loss-of-function mutation in the more than two megabase large dystrophin gene, which leads to the loss of the muscle structure protein of the same name [4,5]. The dystrophin protein, a key component of the dystrophin-associated glycoprotein complex in skeletal muscle cells and cardiomyocytes [4], normally links the actin cytoskeleton to the sarcolemma and the extracellular matrix and provides mechanical stability during contraction as well as mechanosignalling to the extracellular matrix [6,7]. The absence of dystrophin leads to a contraction-induced muscle fibre damage, an altered calcium homeostasis with repeated cycles of de- and regeneration and myoinflammation until the muscle tissue is gradually replaced by fatty and fibrotic tissue [1,8,9]. DMD patients present with progressive skeletal muscle degradation, a loss of ambulation, progressive cardiomyopathy [10] and a reduction in respiratory function [11]. Cardiopulmonary impairment is significantly involved in the premature death of patients [12,13]

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