Dystrophin deficiency impairs cell junction formation during embryonic myogenesis from pluripotent stem cells
Elise Mozin1, Emmanuelle Massouridès2, Virginie Mournetas3
1Nantes Université, CHU Nantes, INSERM, TARGET, F-44000 Nantes, France.
Insights
Duchenne muscular dystrophy (DMD) cells show altered development and cell communication early on. This study reveals how dystrophin deficiency impacts muscle development before symptoms appear, informing future DMD therapies.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- Mutations in the dystrophin (DMD) gene cause Duchenne muscular dystrophy (DMD), a severe condition.
- DMD impacts skeletal muscles before clinical symptoms manifest, complicating early intervention.
- Understanding dystrophin's role during development is crucial for effective therapeutic strategies.
Purpose of the Study:
- To investigate the effects of dystrophin deficiency on skeletal muscle development.
- To characterize the myogenic trajectory in human pluripotent stem cells lacking dystrophin.
- To identify molecular mechanisms underlying developmental defects in DMD.
Main Methods:
- Single-cell transcriptome profiling of human pluripotent stem cells.
- Analysis of myogenic cell trajectories during embryonic development.
- Examination of cell junction protein expression and function.
Main Results:
- Duchenne muscular dystrophy (DMD) cells deviate from normal myogenic trajectory at the somite stage.
- Dystrophin deficiency leads to dysregulation of cell junction proteins.
- Impaired cell-cell communication observed during in vitro myogenic development.
Conclusions:
- Dystrophin deficiency disrupts normal cell-cell communication during myogenic development.
- Early developmental defects in DMD are linked to cell junction abnormalities.
- Findings provide insights for developing novel therapeutic strategies for Duchenne muscular dystrophy.
Abstract:
Mutations in the DMD gene lead to Duchenne muscular dystrophy (DMD), a severe neuromuscular disorder affecting young boys as they acquire motor functions. DMD is typically diagnosed at 2-4 years of age, but the absence of dystrophin has negative impacts on skeletal muscles before overt symptoms appear in patients, which poses a serious challenge in current standards of care. Here, we investigated the consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Dystrophin deficiency was linked to marked dysregulations of cell junction proteins involved in the cell state transitions characteristic of embryonic somitogenesis. Altogether, this work demonstrates that in vitro, dystrophin deficiency has deleterious effects on cell-cell communication during myogenic development, which should be considered in future therapeutic strategies for DMD.
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