Muscular dystrophies are a group of inherited genetic conditions that cause progressive weakness and loss of muscle mass.
Among muscular dystrophies, Duchenne Muscular Dystrophy (DMD) is the most common and most severe form. It is caused by a genetic mutation that induces a lack of dystrophin protein. The defect of this protein leads to progressive muscle degeneration, which is linked to weakening of musculoskeletal muscles and a decline of respiratory and cardiac functions.
No cure currently exists, but various therapeutics approaches are currently being investigated, aiming at compensating for the lack of dystrophin or restoring dystrophin expression.
In 2019, Shimizu-Motohashi Y et al published a review of the current status of the DMD research1.
Several animal models have been developed these last decades, the most widely used being the mdx mice, for gene therapy studies. However, larger animal models such as dog, pig or non-human primate turn out to be relevant and complementary, as their phenotype is closer to DMD patients. Thus, they are usually used during the last preclinical validation step.
For instance, the Golden Retriever model of Muscular Dystrophy (GRMD) plays an important role in characterizing complications of pharmacologic intervention and immunologic reactions to cell and gene therapies2.
Respiratory failure is a major cause of death amongst patients with neuromuscular dystrophies, and an improvement of this vital parameter represents an indispensable requisite for a life-improving therapy.
In large animals, respiratory function can be assessed non-invasively by Respiratory Inductance Plethysmography (RIP).
RIP technique uses belt(s) placed around the subject’s thorax and/or abdomen. Each belt consists of a copper wire through which a current is passed. The wave shape of the wire enables stretching and contraction of the belt as the subject breathes. Changes in the cross-sectional area of the torso lead to changes in the belt’s inductance. The inductance is then converted into lung volume.
In rodent models, respiratory function can be measured by whole body plethysmography, as shown below in a mice model of Duschenne Muscular Dystrophy3.
In this study published in March 2022, Antoine de Zélicourt et al investigated the role of CD38 on the heart function and skeletal muscle performances.
CD38 is an ecto-enzyme producing modulators of Ca2+ channels from extracellular Nicotinamide Adenine Dinucleotide (NAD+). They observed that the inactivation of CD38 led to an improved skeletal muscle performance and heart function, suggesting a potential therapy for DMD, but also associated cardiovascular pathologies, such as heart failure and cardiomyopathy.
In combination to the assessment of the respiratory function, it is important to add ECG measurement to evaluate the associated cardiomyopathy leading to heart failure as it represents the main cause of patient death.
Non-invasive ECG recording in rodents can be performed by placing the subject in a cylinder-shaped tube to gently restrains the animal, allowing the paws to be in contact with electrode pads. Placing a plethysmograph dome above the tunnel allows to get respiratory endpoints, simultaneously assessing both the respiratory and cardiac pathology.
Similarly, in large animals, external ECG electrodes can be added to the RIP measurement on jacketed subjects, for snapshot or long-term acquisition. Using wireless telemetry, emkaPACK5 system allows to gather data continuously, for longer periods of time, from animals residing in their own familiar environment, thus minimizing stress to the animals and consequent experimental artifacts.
This non-invasive method avoids complications encountered with the use of anesthesia, and surgery on fragile subjects. The subject global activity is also provided, making it very complementary to other classic tests, such as dysphagia, ptyalism, hypertrophy of the base of the tongue or mouth opening, made following a treatment to quantify clinical improvement of DMD subjects.
Some DMD patients also encounter cognitive and emotional problems.
Amel Soudi et al recently investigated the emotional behavior and fear learning performance of mdx52 mice, a model of Duchenne muscular dystrophy (DMD) lacking brain dystrophins Dp427 and Dp1405.
After a macroscopic study of brain morphology by magnetic resonance imaging and neurohistology, behavioral outcome such as locomotor activity, anxiety, fear, learning, and memory were measured during various tests (open field, elevated plus-maze, auditory-cued fear conditioning, etc.).
Her findings suggest an enhanced anxiety and a different pattern of impairment of conditioned fear, in this model, compared to the original mdx model, only lacking Dp427.
To understand the underlying neurobiological mechanisms in patients with a comparable genetic profile, further preclinical studies may involve neurobehavioral recordings. Advances in telemetry now offers ways to assess subtle changes in neuron electrical current in EEG while simultaneously performing behavioral tests.
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