Natural disease history of the D2‐mdx mouse model for Duchenne muscular dystrophy

Abstract

The C57BL/10ScSn‐Dmdmdx/J (BL10‐mdx) mouse has been the most commonly used model for Duchenne muscular dystrophy (DMD) for decades. Their muscle dysfunction and pathology is, however, less severe than in patients with DMD, which complicates preclinical studies. Recent discoveries indicate that disease severity is exacerbated when muscular dystrophy mouse models are generated on a DBA2/J genetic background. Knowledge on the natural history of animal models is pivotal for high‐quality preclinical testing. However, for BL10‐mdx mice on a DBA2/J background (D2‐mdx), limited data are available. We addressed this gap in the natural history knowledge. First, we compared histopathological aspects in skeletal muscles of young D2‐mdx, BL10‐mdx, and wild‐type mice. Pathology was more pronounced in D2‐mdx mice and differed in severity between muscles within individuals. Secondly, we subjected D2‐mdx mice to a functional test regime for 34 weeks and identified that female D2‐mdx mice outperform severely impaired males, making females less useful for functional preclinical studies. Direct comparisons between 10‐ and 34‐wk‐old D2‐mdx mice revealed that disease pathology ameliorates with age. Heart pathology was progressive, with some features already evident at a young age. This natural history study of the D2‐mdx mouse will be instrumental for experimental design of future preclinical studies.—Van Putten, M., Putker, K., Overzier, M., Adamzek, W. A., Pasteuning‐Vuhman, S., Plomp, J. J., Aartsma‐Rus, A. Natural disease history of the D2‐mdx mouse model for Duchenne muscular dystrophy. FASEB J. 33, 8110–8124 (2019). http://www.fasebj.org

Skeletal muscle in health and disease

“…Skeletal muscle pathology of the gamma-sarcoglycan (Sgcg)-null mouse model (Box 1) of limb-girdle muscular dystrophy (LGMD) is worse in a DBA2/J than a 129/SVemst/J genetic background (Fukada et al, 2010;Heydemann et al, 2009). Likewise, the DBA2/J background is associated with a worse mdx pathology than the C57Bl/10 background (Fukada et al, 2010;Coley et al, 2016;van Putten et al, 2019) (Box 1). Furthermore, genetic modifiers (Box 1) in DMD and facioscapulohumeral muscular dystrophy affect membrane-associated proteins that may preserve muscle fibres against degeneration (reviewed in Hightower and Alexander, 2018).…”

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

“…The choice of readouts and biomarkers needs to be tailored to the drug tested and to the expected efficacy, both on the molecular level and for functional, clinically relevant aspects. Notably, as in human trials, preclinical studies can only be properly planned when the natural history of the model system is known (see for example Gordish-Dressman et al, 2018;van Putten et al, 2019;Verhaart et al, 2019), as this will also guide researchers in determining when to start the intervention and when and how to assess its therapeutic effects.…”

240th ENMC workshop: The involvement of skeletal muscle stem cells in the pathology of muscular dystrophies 25–27 January 2019, Hoofddorp, The Netherlands

“…D2mdx mice have lower counts of centralized nuclei and active regeneration (BrdU and eMHC staining). A striking difference between the strains is extensive calcified muscles in D2mdx mice [23] . These seem to be directly linked to muscle damage, differ in abundance between muscles and these calcifications ameliorate with age (very abundant in 10 week old mice, but much reduced numbers at 34 weeks of age).…”