Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

• Published in: The Journal of clinical investigation 2020-05, Vol.130 (5), p.2465-2477
• Main Authors: Bosnakovski, Darko, Shams, Ahmed S, Yuan, Ce, da Silva, Meiricris T, Ener, Elizabeth T, Baumann, Cory W, Lindsay, Angus J, Verma, Mayank, Asakura, Atsushi, Lowe, Dawn A, Kyba, Michael
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Binding sites; Biomedical research; Biopsy; Chronic diseases; Chronic illnesses; Degeneration; Diagnostic imaging; Disease Models, Animal; Diseases; Endothelial cells; Endothelial Progenitor Cells - metabolism; Endothelial Progenitor Cells - pathology; Endothelium; Female; Fibrosis; Force; Gene expression; Gene Expression Regulation; Genes; Genetic aspects; Histochemistry; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Humans; Magnetic resonance imaging; Mice; Mice, Transgenic; Muscle function; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular dystrophy; Muscular Dystrophy, Facioscapulohumeral - genetics; Muscular Dystrophy, Facioscapulohumeral - metabolism; Muscular Dystrophy, Facioscapulohumeral - pathology; Pathology; Physiology; Proteins; Stem cells; Transcription; Transcription (Genetics); Transcription, Genetic
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI133303

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.