Spontaneous rhabdomyosarcomas in Dmd mdx rats

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 (Dmd ^mdx ) 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 Dmd ^mdx 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.