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Biomarkers for Duchenne Muscular Dystrophy: Myonecrosis, Inflammation and Oxidative Stress Miranda D

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Biomarkers for Duchenne Muscular Dystrophy: Myonecrosis, Inflammation and Oxidative Stress Miranda D © 2020. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2020) 13, dmm043638. doi:10.1242/dmm.043638 REVIEW Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress Miranda D. Grounds1,*, Jessica R. Terrill2, Basma A. Al-Mshhdani2, Marisa N. Duong2, Hannah G. Radley-Crabb3 and Peter G. Arthur2 ABSTRACT worldwide, causing severe loss of muscle mass and function, with Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease death often occurring in the late teens due to respiratory or cardiac that causes severe loss of muscle mass and function in young failure (Bushby et al., 2010; Falzarano et al., 2015; Partridge, 2011). DMD children. Promising therapies for DMD are being developed, but the is the largest gene in the human genome and encodes at least long lead times required when using clinical outcome measures are seven distinct proteins; one of which, the dystrophin isoform hindering progress. This progress would be facilitated by robust Dp427, is found in skeletal and cardiac muscle. All dystrophin molecular biomarkers in biofluids, such as blood and urine, which isoforms bind to a dystroglycan complex (DGC) in the cell could be used to monitor disease progression and severity, as well as membrane (Waite et al., 2012). In skeletal muscles, dystrophin is to determine optimal drug dosing before a full clinical trial. Many located beneath the sarcolemma (Box 1, Glossary) and links the actin candidate DMD biomarkers have been identified, but there have been cytoskeleton and the specialised contractile proteins in the sarcoplasm few follow-up studies to validate them. This Review describes the (Box 1) to the transmembrane DGC that spans the sarcolemma to promising biomarkers for dystrophic muscle that have been identified connect with laminin and a network of extracellular matrix (ECM) in muscle, mainly using animal models. We strongly focus on molecules, including collagens, to transfer the contractile muscle myonecrosis and the associated inflammation and oxidative stress force and move parts of the skeleton. Dystrophin is enriched at the in DMD muscle, as the lack of dystrophin causes repeated bouts of costameres and myotendinous junctions (MTJs; Box 1) where force myonecrosis, which are the key events that initiate the resultant is transmitted across the cell membrane (Ridge et al., 1994; Zhao severe dystropathology. We discuss the early events of intrinsic et al., 1992). Dystrophin is also involved in various signalling myonecrosis, along with early regeneration in the context of pathways (Allen et al., 2016). DMD histological and other measures that are used to quantify its Mutations in causing a lack of functional dystrophin result incidence. Molecular biomarkers linked to the closely associated in a fragile sarcolemma that is susceptible to damage after skeletal events of inflammation and oxidative damage are discussed, with a muscle contraction, leading to intrinsic myofibre necrosis (or focus on research related to protein thiol oxidation and to neutrophils. myonecrosis). Necrosis is closely associated with increased We summarise data linked to myonecrosis in muscle, blood and urine inflammation and oxidative stress (Tidball et al., 2018), and leads of dystrophic animal species, and discuss the challenge of translating to subsequent regenerative myogenesis (Fig. 1). Repeated bouts of such biomarkers to the clinic for DMD patients, especially to enhance myonecrosis also cause increased fibrosis over time (Allen et al., the success of clinical trials. 2016; Biggar, 2006; Bushby et al., 2010; Emery, 2002; Falzarano et al., 2015; Grounds, 2008; Kharraz et al., 2014; Kim et al., 2013; KEY WORDS: DMD, Dystrophic mice, Rats, Dogs, Biomarkers, Renjini et al., 2012). Intrinsic myonecrosis of skeletal muscles is Blood, Urine, Muscle necrosis, Inflammation, Neutrophils, central to the progressive dystropathology of DMD and appears Oxidative stress to be exacerbated by growth, exercise and metabolism, associated with unmet high energy needs (Radley-Crabb et al., 2014). In Introduction: pathophysiology of Duchenne muscular addition, the progressively increasing fibrosis caused by repeated dystrophy bouts of myonecrosis and inflammation impairs myogenesis Developing robust biomarkers for a disease requires comprehensive and regeneration of DMD muscles, with resultant severe loss of information about the human condition and the associated muscle tissues. animal models. Duchenne muscular dystrophy (DMD) is a lethal, Bouts of intrinsic myonecrosis in DMD can also directly damage X chromosome-linked muscle disease caused by mutations in the neuromuscular junctions (NMJs; Box 1). The adverse progressive dystrophin (DMD) gene, which result in the loss or altered function changes in NMJs, which indicate denervation, are widely reported of dystrophin protein. DMD affects about 1 in 3500-6000 boys in dystrophic muscles of rodent and dog models of DMD (Haddix et al., 2018). These altered NMJs affect the associated dystrophic nerve over time, with consequent increased levels of S100 and 1School of Human Sciences, the University of Western Australia, Perth, WA 6009, Australia. 2School of Molecular Sciences, the University of Western Australia, Perth, Tau5 proteins seen by 13 months of age in sciatic nerves of mdx WA 6009, Australia. 3School of Pharmacy and Biomedical Sciences, Curtin Health mice (Gordish-Dressman et al., 2018). Such neuronal changes and Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia. indicate progressive irreversible denervation, often associated with neurodegeneration (Krishnan et al., 2016), that is likely to *Author for correspondence ([email protected]) become pronounced over many years or decades and contribute to M.D.G., 0000-0002-4530-9402 the loss of muscle function in DMD patients. These preclinical neuronal changes could prove useful as a biomarker for the long- This is an Open Access article distributed under the terms of the Creative Commons Attribution term consequences of repeated intrinsic myonecrosis in animal License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. studies. Disease Models & Mechanisms 1 REVIEW Disease Models & Mechanisms (2020) 13, dmm043638. doi:10.1242/dmm.043638 resonance imaging (MRI) in humans and animal models of DMD Box 1. Glossary (Szigyarto and Spitali, 2018). Although MRI is increasingly being Costamere. The structural-functional component of striated myofibres used as a powerful tool for measuring outcome without the need for that links the sarcomere to the cell membrane. muscle biopsy, its repeated use has limitations, including expensive Creatine kinase (CK). Enzyme expressed in muscle and other tissues equipment and expertise, high cost per measurement and that catalyses the conversion of creatine to phosphocreatine and inconvenience for the patient due to the immobilisation and time adenosine diphosphate. Myoglobin. Iron- and oxygen-binding protein found in myofibres; required for repeated measurements (Szigyarto and Spitali, 2018). particularly abundant in slow muscles, which are better suited to derive For therapies using a drug that targets a specific molecular signalling their energy by oxidative phosphorylation. pathway, it is clearly desirable to monitor the predicted changes in Myotendinous junctions (MTJs). Site of connection between tendon proteins or RNAs within that pathway to demonstrate drug and muscle. target engagement and efficacy. However, such drug-specific Neuromuscular junctions (NMJs). Site of the transmission of action pharmacodynamic biomarkers fall outside the scope of the present potential from nerve to muscle. Nitric oxidase synthase (NOS). Enzyme catalysing the production of discussion. nitric oxide. Diverse dystrophic animal models are used to study DMD, Sarcolemma. Cell membrane of a striated myofibre. ranging from the classic mdx mouse (Coulton et al., 1988; Partridge, Sarcoplasm. Cytoplasm of a striated myofibre. 2013) and the important larger dystrophic dog models such as 6-min walk test. A clinical test protocol that measures the total distance golden retriever muscular dystrophy (GRMD) with more severe DMD patients are able to walk in 6 min. disease manifestation (reviewed by Kornegay, 2017), to dystrophic Xanthine oxidase. Enzyme that catalyses the oxidation of hypoxanthine Dmdmd to xanthine and can further catalyse the oxidation of xanthine to uric acid. rats (Larcher et al., 2014), rabbits (Sui et al., 2018), pigs, cats, zebrafish and fruit flies (reviewed by Wells, 2018). Although human blood and urine samples can be fairly easily obtained for analyses, muscle biopsy is highly invasive and undesirable for A key aim for DMD therapies is to prevent myonecrosis and to DMD patients. Thus, data from diverse tissue samples of animal directly stabilise the myofibres, ideally by replacing the non- models provide the basis for much of the following discussion. functional dystrophin using various gene delivery or molecular strategies, with recent promising progress (Verhaart and Aartsma- Overview of molecular biomarkers, especially for Rus, 2019). In parallel, there is interest in optimising therapies to myonecrosis and associated events either prevent or reduce myonecrosis, or target the associated events Many biomarkers of potential interest for DMD that reflect the of inflammation, oxidative
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