Murine models of Duchenne muscular dystrophy: is there a best model?

Abstract

ViewpointMurine models of Duchenne muscular dystrophy: is there a best model?Kristy Swiderski and Gordon S. LynchKristy SwiderskiCentre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia and Gordon S. LynchCentre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Melbourne, Victoria, AustraliaPublished Online:09 Aug 2021https://doi.org/10.1152/ajpcell.00212.2021This is the final version - click for previous versionMoreSectionsPDF (845 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Duchenne muscular dystrophy (DMD) is a debilitating X-linked recessive skeletal muscle-wasting disorder affecting 1 in 3,500–6,000 live-born males. Despite mutations in the dmd gene and a subsequent lack or aberrant expression of the dystrophin protein being identified over 30 years ago as the underlying cause of the disease, there remains no cure (1). Treatment efficacy, particularly of pharmacological approaches to attenuate symptoms, is often compromised by the severity of the pathology, which is characterized by a progressive loss of muscle fibers and concomitant replacement by connective tissue and fat. Gene-based and/or cell-based therapies to replace the defective or absent dystrophin protein are possible options to cure DMD. To date, five drugs have been approved by the Food and Drug Administration (FDA) to treat DMD, including a glucocorticoid (deflazacort) to address aspects of the pathology, and four antisense oligonucleotide (AON) therapies. Exondys 51 (eteplirsen), the first AON approved by the FDA, was proven safe in preclinical studies in dystrophic mice and cynomolgus monkeys (2, 3), and exon 51 skipping was later shown to be efficacious in restoring dystrophin expression in dystrophic mice (4). In clinical trials, the variable efficacy of eteplirsen has been attributed to genotype differences between patients (3).Preclinical studies in appropriate models of DMD are critical for the development and testing of novel therapies. In vitro models using patient-derived myoblasts and more recently, induced pluripotent stem cells, are useful for testing muscle-intrinsic improvements after dystrophin restoration, but cannot model systemic physiological responses (reviewed in Ref. 5). Multiple animal models of DMD have been identified/generated, including zebrafish (6), dogs (7), and rodents (8–15). Dystrophin-deficient zebrafish have proved useful for undertaking high-throughput in vivo drug screens, but their translation to human physiology is limited (6). Dystrophin deficiency has been identified in various dog breeds, including the golden retriever muscular dystrophy (GRMD) model, which can closely mimic aspects of the human disease (7). Disadvantages of the GRMD model include the considerable phenotypic variation between dogs (necessitating higher animal numbers in experiments) and their large size, making them cost prohibitive for most preclinical investigations. Rodent models are particularly advantageous as mammalian preclinical models due to their relatively small size, ease of use, and cost effectiveness. Murine models of DMD are the most widely used, although more recently, dystrophin deficiency has been modeled in the rat using transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) technologies, producing phenotypic features like that in DMD (14, 15). Whether rat models are superior to mouse models for studying DMD remains a question of interest, but choosing the most appropriate murine model for investigation remains a key consideration for researchers studying the pathophysiology of muscular dystrophy (Fig. 1).Figure 1.Most commonly studied murine models of DMD. Three murine models of DMD include the C57BL/10ScSn mdx, mdx/utrn−/− (dko), and D2.mdx mouse, which are commonly used for studying the pathophysiology of DMD. Each model has specific advantages and disadvantages that must be considered when choosing the most appropriate mouse model for investigation. Combined, these mouse models cover a range of disease severity across various skeletal muscles, and provide appropriate experimental platforms for preclinical studies, particularly for evaluating the therapeutic potential of pharmacologic-mediated, gene-mediated, and/or cell-mediated strategies to treat and ultimately cure the disease. Created with BioRender.com. DMD, Duchenne muscular dystrophy.Download figureDownload PowerPointThe C57BL/10ScSn mdx mouse is the most commonly used animal model of DMD, having a naturally occurring point mutation in exon 23 of the dmd gene and an absence of the full-length dystrophin Dp427 protein isoform (9). Unlike DMD, the limb muscles of C57BL/10ScSn mdx mice exhibit a mild pathology, characterized by an initial significant bout of muscle fiber degeneration at 3–4 wk of age, followed by highly effective regeneration that essentially outpaces the degeneration, resulting in hypertrophy of affected limb muscles. Despite being larger, the intrinsic force-producing capacity of these muscles is typically lower than that of muscles from wild-type control mice (16). The mild muscle pathology in C57BL/10ScSn mdx mice is largely attributed to a compensatory upregulation of the dystrophin-related protein, utrophin. Although this confers some protection, muscles of C57BL/10ScSn mdx mice remain fragile and susceptible to contraction-mediated damage (16, 17). The diaphragm in C57BL/10ScSn mdx mice is severely affected and more closely resembles the DMD pathology, with progressive muscle fiber degeneration and concomitant connective tissue infiltration (17). Older mdx mice exhibit greater impairments in muscle strength, spinal deformities including kyphosis, cardiomyopathy, and impaired muscle regeneration. However, unlike the premature death associated with DMD, the lifespan of C57BL/10ScSn mdx mice is essentially normal. Despite these limitations, the C57BL/10ScSn mdx mouse remains a suitable model for understanding how a lack of dystrophin affects striated muscles and other tissues, including the gastrointestinal tract, bone, and nervous system (18–20). Furthermore, the mechanisms responsible for the enhanced muscle regenerative capacity in C57BL/10ScSn mdx mice may provide insights into developing strategies to improve muscle regeneration in DMD.To overcome the experimental limitations of using C57BL/10ScSn mdx mice, alternative murine models have been generated that more closely resemble the DMD phenotype, including the D2.mdx mouse and the dystrophin/utrophin double-deficient (dko) mouse. Although the genetic basis of the dko mouse is not a genocopy of the human disease due to its different genetic deletions, the loss of utrophin in addition to dystrophin deficiency more closely phenocopies the dystrophic pathology in DMD, including progressive degeneration of the limb and diaphragm muscles, early-onset kyphosis, and premature death (13). Using both C57BL/10ScSn mdx and dko mouse models can be an effective approach for studying the dystrophic pathology and evaluating the efficacy of interventions across a “therapeutic window” of the disease progression (21, 22). Other double-knockout models have been generated with deletion of either MyoD, α-dystrobrevin, or α7-integrin on the mdx background and these have been reviewed elsewhere (23, 24). Although these models are useful for understanding the role of these proteins in muscle biology, they do not accurately recapitulate the genetics of human disease.More recently, the C57BL/10ScSn mdx mouse was bred onto the DBA/2J genetic background to generate D2.mdx mice (11). D2.mdx mice are genetically similar to DMD, but exhibit more extensive degeneration and less successful regeneration within the diaphragm and limb muscles, with extensive fibrotic infiltration, making them a closer phenocopy of DMD. This is attributed to a polymorphism in the latent transforming growth factor β binding protein (LTBP) 4 gene, identified previously as a genetic modifier of disease severity in patients with DMD and associated with increased fibrosis (25). Comparisons of the pathophysiology between D2.mdx and C57BL/10ScSn mdx mice from 4 to 12 mo of age indicate that a more severe pathology in D2.mdx mice makes them a better model of DMD (26). However, unlike in DMD, the D2.mdx mouse develops calcifications within its skeletal muscles, particularly the diaphragm, which has been attributed to active osteogenesis (26–28). This can be problematic when quantifying fibrosis, a key marker for evaluating therapeutic efficacy.Despite their limitations, each mouse model provides a useful platform for testing viral-mediated gene therapies and pharmacologics, including antifibrotic approaches. However, their usefulness for testing gene-editing strategies, particularly exon skipping, is limited since they all contain the same dmd mutation. CRISPR/Cas9 technology has therefore been used to generate dystrophin mutations at other sites of the dmd gene relevant to patients (12, 29) with DMD, with special relevance for testing AONs as disease modifiers. In 1989, N-ethyl-N-nitrosourea (ENU) chemical mutagenesis was used to generate four chemical variants (cv) of the C57BL/10ScSn mdx mouse, named mdx2cv, mdx3cv, mdx4cv, and mdx5cv, in an effort to expand the pool of available mouse models of DMD (10). The mdx52 mouse was generated via targeted deletion of exon 52 to model mutations in a known DMD “hot spot” (8). All mutants have similar pathophysiology to C57BL/10ScSn mdx mice with minor differences (30, 31), but each has merits for testing specific hypotheses. The characterization of additional novel dmd mutant mice using these strategies will be essential for preclinical evaluation of AONs to treat patients with DMD with mutations across the span of the dmd gene.Recent studies published in the American Journal of Physiology-Cell Physiology highlight that there is still much to learn about the dystrophic pathology from using different murine models. Lopez et al. (32) confirmed the age-related deterioration of diaphragm muscle structure and function in mdx mice, demonstrating that changes in tissue compliance were attributed to the progressive replacement of viable muscle fibers with connective tissue. The findings have implications relevant to gene-mediated and cell-mediated therapies for DMD since they highlight how progressive replacement of viable muscle fibers with noncontractile tissue limits the available material (muscle fibers) to be transduced by gene therapies and how fibrosis poses a physical barrier that potentially compromises cell transplantation therapies. Young et al. (33) showed that cellular senescence contributes to the pathophysiology in C57BL/10ScSn mdx and D2.mdx mice, with senescence evident in macrophages and endothelial cells, and the number and location of senescent cells differing between mouse strains. Of specific interest, they demonstrated a lack of senescence in Pax7-positive muscle stem cells in either mouse model (33), in contrast to reports in a rat model of DMD (34). Together, these studies demonstrate there is still much to learn from studying the pathophysiology of C57BL/10ScSn mdx mice, and that using more than one model is a powerful approach for better understanding and treating DMD.Although no perfect murine model of DMD currently exists, researchers should recognize the relative advantages and disadvantages of the different available models when studying the dystrophic pathophysiology and/or devising novel interventions to ameliorate the pathology or correct the genetic deletion. More than one model may be required for the comprehensive tests needed to advance novel therapeutics to the clinic.GRANTSThis work was supported by the Department of Health, Australian Government, National Health and Medical Research Council Grants GNT1041865 and GNT1144772 (to G.S. Lynch).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSK.S. and G.S.L. drafted manuscript; edited and revised manuscript; approved final version of manuscript.ACKNOWLEDGMENTSThere is a vast literature relevant to this topic and we apologize to authors whose work could not be cited because of the strict space limitations.REFERENCES1. Hoffman EP, Brown RH, Jr., Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51: 919–928, 1987. doi:10.1016/0092-8674(87)90579-4. Crossref | PubMed | ISI | Google Scholar2. Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 11: 533–545, 2017. doi:10.2147/DDDT.S97635. Crossref | PubMed | ISI | Google Scholar3. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. 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Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy. Sci Rep 10: 16385, 2020. doi:10.1038/s41598-020-73315-6. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESCorrespondence: G. S. Lynch ([email protected]edu.au). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByUrine titin as a novel biomarker for Duchenne muscular dystrophyNeuromuscular Disorders, Vol. 33, No. 4Nanomedicine for Treating Muscle Dystrophies: Opportunities, Challenges, and Future Perspectives10 October 2022 | International Journal of Molecular Sciences, Vol. 23, No. 19Mitochondrial stress responses in Duchenne muscular dystrophy: metabolic dysfunction or adaptive reprogramming?Catherine A. Bellissimo, Madison C. Garibotti, and Christopher G. R. 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