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Spontaneous rhabdomyosarcomas in Dmdmdx rats
Rachel H Moore1, SiWei Luo1, Aude Lafoux2,3
1University of Washington, Seattle, WA.
Abstract:
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder primarily affecting male children and resulting in progressive degeneration and attempted regeneration of muscle with replacement of myofibers by adipose and fibrotic tissue. DMD patients have mutations in the DMD gene encoding for the large cytoskeletal protein dystrophin, which plays an essential role in the dystrophin-glycoprotein complex (DGC) as a structural connector within cardiac and skeletal muscle. The absence of dystrophin and DGC proteins leads to increased membrane fragility, dysregulation of calcium homeostasis, oxidative damage in muscle cells, and finally, premature death of the patients. Rhabdomyosarcoma (RMS), a soft tissue sarcoma arising from subpopulations of muscle cells and their precursors, has previously been reported in DMD patients and mouse models of DMD. Here, we report a case series of RMS arising from skeletal muscles in a Dmd-mutated (Dmdmdx) rat model developed using transcription activator-like effector nucleases targeting exon 23 of the Dmd gene on a Sprague Dawley background. Subcutaneous firm masses were noted grossly in 8 male Dmdmdx rats aged 6 to 17 months. The histologic findings were consistent with a sarcoma of skeletal muscle, with a population of small round cells in addition to spindle-shaped cells and occasional large multinucleated cells. The neoplasms were immunoreactive for myogenin, MyoD1, and desmin. Histology and immunohistochemistry supported the diagnosis of RMS. This represents a potentially novel animal model of DMD-associated RMS.
Insights
Duchenne muscular dystrophy (DMD) is a genetic disorder causing muscle degeneration. Researchers developed a new rat model that developed rhabdomyosarcoma (RMS), a type of muscle cancer, offering a novel model for studying DMD-associated RMS.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Animal Models
Background:
- Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, leading to dystrophin deficiency.
- Dystrophin is crucial for muscle integrity within the dystrophin-glycoprotein complex (DGC).
- Rhabdomyosarcoma (RMS) has been observed in DMD patients and mouse models, suggesting a link between DMD and RMS development.
Purpose of the Study:
- To report a case series of rhabdomyosarcoma (RMS) in a novel Duchenne muscular dystrophy (DMD) rat model.
- To characterize the development and histological features of RMS in this DMD rat model.
- To establish a potentially new animal model for studying DMD-associated RMS.
Main Methods:
- Development of a Duchenne muscular dystrophy (DMD) rat model using CRISPR-Cas9 technology targeting exon 23 of the Dmd gene.
- Gross examination of 8 male Dmd-mutated rats aged 6-17 months for subcutaneous masses.
- Histological and immunohistochemical analysis of the observed masses to diagnose rhabdomyosarcoma (RMS).
Main Results:
- Subcutaneous firm masses were identified in 8 male Dmd-mutated rats.
- Histological findings were consistent with skeletal muscle sarcoma, showing small round cells, spindle-shaped cells, and multinucleated cells.
- Immunohistochemistry confirmed the diagnosis of RMS, with neoplasms immunoreactive for myogenin, MyoD1, and desmin.
Conclusions:
- A novel Duchenne muscular dystrophy (DMD) rat model spontaneously developed rhabdomyosarcoma (RMS).
- This rat model exhibits histological and immunohistochemical features consistent with RMS.
- This study presents a potentially valuable new animal model for investigating the relationship between DMD and RMS.
