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#apaperaday: The X-linked Becker muscular dystrophy (bmx) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45–47

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: The X-linked Becker muscular dystrophy (bmx) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45–47

Today’s pick is from the journal of cachexia, sarcopenia and muscle by Heier et al on a mouse model for Becker muscular dystrophy. DOI: 10.1002/jcsm.13171.

Becker muscular dystrophy (BMD) is caused by mutations in the dystrophin gene that allow production of partially functional dystrophins. It is less severe than Duchenne (where no functional dystrophins can be produced), but still a progressive debilitating disease.

There is a lot of variability between age of ones of muscle and/or heart pathology between Becker patients, even within families. The disease is understudied and no mouse model was available. Here authors have generated and characterized a Becker mouse model.

Authors call the model bmx (Becker muscular dystrophy, X-linked). The model was generated with genome editing (Crispr/cas9) and carries the most common deletion found in Becker patients: a deletion of exon 45-47.

The model was compared to wild types AND to mdx mice – very good! The model produces dystrophin but at reduced levels (analyzed with ProteinSimple WES). bmx mice show reduced strength and function compared to wild type butt do better than mdx mice

In muscle physiology there is a force drop after eccentric exercise but also less than mdx mice. Authors studied heart function in 18 month old mice, revealing reduced ejection fraction compared to wild type. They also see dystrophic pathology on histology.

They see variability in fiber size. Also here bmx mice are more similar to wild types than mdx, but still there is clear pathology. Authors show active regeneration, fibrosis and inflammation in bmx muscle. nNOS was absent at the membrane, while other DGC components were reduced.

Authors study dystrophin mRNA levels and protein levels and see a discrepancy: protein levels are reduced, while mRNA levels are normal compared to wild type. HOWEVER, authors look at exon 76-77 for the mRNA and this is part of the muscle form but also the Dp71 form.

Dp71 is expressed in inflammatory and fibrotic cells. I would recommend checking exons early in the Dp427m (exon 1 etc) and exon junctions after the deletion but before the start of Dp71 (exon 50 and exon 60 e.g.). Predict exon 1 will be same as wild type and exon 50/60 reduced.

See also these papers if you want to know more about transcript imbalance: https://pubmed.ncbi.nlm.nih.gov/23975932/ and https://pubmed.ncbi.nlm.nih.gov/32616572/ by Pietro Spitali.

Back to the paper: authors present the first BMD mouse model and have done a lot of work already to characterize it. More work is needed – authors outline studies to assess the development of heart problems but also studies to test therapeutic compounds in Becker rather or on top of Duchenne mouse models. These are possible now that a Becker model is finally there.

Authors discuss that the model suggests that 20-30% of dystrophin appears enough for a slower progression as evidenced by their mouse model. However, for therapies aiming to allow Duchenne patients to make Becker dystrophin we have to bear in mind that we intervene later.

Becker patients and mice have dystrophin from birth while in Duchenne it is restored only at the time of intervention. Kudos to the authors for making the model and analyzing it so diligently with mdx and wild type references!