Journal
SCIENCE ADVANCES
Volume 7, Issue 37, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abi8787
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Funding
- Wellcome Trust [108874/Z/15/Z, WT098051]
- QMUL-Blizard PhD studentship
- Muscular Dystrophy U.K. [17GROPG36-0165]
- Medical Research Council [MR/N025865/1, G0802546/1]
- Royal Society [RG130417]
- Newlife Charity [SG/14-15/14]
- Action Duchenne grant [AD1801Y]
- Duchenne Parent Project grant [19.017]
- Barts Charity grant [MGU0426]
- Cancer Research UK Centre of Excellence Award to Barts Cancer Centre grant [C16420, A18066]
- Medical Research Council Centre grant [MR/N026063/1]
- QMUL-Life Sciences Initiative grant
- Medical Research Council [MR/N025865/1] Funding Source: researchfish
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The study combines transcriptome analysis and modeling of neuromuscular circuits from DMD patients, revealing compromised NMJ volumes and myofiber contraction in DMD patients, which can be rescued by pharmacological inhibition of TGF. signaling. These beneficial effects are associated with normalization of dysregulated gene expression in DMD myogenic transcriptomes affecting NMJ assembly.
Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abnormalities contribute to DMD pathogenesis remains unclear. Here, we combine transcriptome analysis and modeling of DMD patient-derived neuromuscular circuits with CRISPR-corrected isogenic controls in compartmentalized microdevices. We show that NMJ volumes and optogenetic motor neuron-stimulated myofiber contraction are compromised in DMD neuromuscular circuits, which can be rescued by pharmacological inhibition of TGF. signaling, an observation validated in a 96-well human neuromuscular circuit coculture assay. These beneficial effects are associated with normalization of dysregulated gene expression in DMD myogenic transcriptomes affecting NMJ assembly (e.g., MUSK) and axon guidance (e.g., SLIT2 and SLIT3). Our study provides a new human microphysiological model for investigating NMJ defects in DMD and assessing candidate drugs and suggests that enhancing neuromuscular connectivity may be an effective therapeutic strategy.
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