Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

Abstract

Duchenne and Becker muscular dystrophies (DMD/BMD) are neuromuscular disorders that primarily affect boys due to an X-linked mutation in the DMD gene, resulting in reduced to near absence of dystrophin or expression of truncated forms of dystrophin. Some newer therapeutic interventions aim to increase sarcolemmal dystrophin expression, and accurate dystrophin quantification is critical for demonstrating pharmacodynamic relationships in preclinical studies and clinical trials. Current challenges with measuring dystrophin include the variation in protein expression within individual muscle fibers and across whole muscle samples, the presence of pre-existing dystrophin-positive revertant fibers, and trace amounts of residual dystrophin. Immunofluorescence quantification of dystrophin can overcome many of these challenges, but manual quantification of protein expression may be complicated by variations in the collection of images, reproducible scoring of fluorescent intensity, and bias introduced by manual scoring of typically only a few high-power fields. This review highlights the pathology of DMD/BMD, discusses animal models of DMD/BMD, and describes dystrophin biomarker quantitation in DMD/BMD, with several image analysis approaches, including a new automated method, that evaluates protein expression of individual muscle fibers.

Evaluation of the gastrointestinal tract in mdx mice: an experimental model of Duchenne muscular dystrophy

“…Stem cell models and non‐mammalian models also have roles in understanding disease pathogenesis and the effects of treatments on disease pathophysiology. While each model has its limitations, the following model systems have significantly contributed to our understanding of DMD .…”

“…In the later stages of the disease, the skeletal, cardiac and smooth muscle fibers are replaced by fat and fibrous tissue . Clinical descriptions of the disorder focus principally on skeletal and cardiac muscle degeneration; however, gastrointestinal function in DMD has not been rigorously studied .…”

Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress

“…One major cellular consequence of oxidant exposure is irreversible damage to proteins and lipids. These are measured by assaying for carbonyls and damaged lipids such as malondialdehyde and isoprostanes (Wilson et al, 2017), which are all elevated in DMD muscle (Haycock et al, 1996;Kar and Pearson, 1979;Mechler et al, 1984;Renjini et al, 2012). Muscles of mdx mice show significantly elevated levels of protein carbonyls (but not malondialdehyde) by 24 days of age, as do GRMD dogs by 8 months of age (El-Shafey et al, 2011;Terrill et al, 2016b).…”

Change of life span and muscles structure in Drosophila melanogaster distrophy mutants under the influence of N-acetylcystein

“…This disease is characterized by inflammation and necrosis of muscle fibers as well as oxidative stress. Admission of corticosteroids remains the standard therapeutic method of MDD treatment [8,14], and although they produce minor improvements in muscle strength and muscle function, numerous side effects associated with long-term steroid therapy require the study of alternative treatments. The gene-therapeutic methods of treatment of this disease are expensive and inaccessible to many patients.…”

“…М'язова дистрофія Дюшена та м'язова дистрофія Беккера -найважчі форми дистрофій. Поступова деградація скелетних, дихальних і серцевого м'язів спричиняє передчасну смерть хворих [14]. Причиною виникнення цих міопатій є мутації в гені дистрофіну, які призводять до появи білків із вкороченою структурою або до повної відсутності білка дистрофіну.…”