A human pluripotent stem cell model of FSHD-affected skeletal muscles

Facioscapulohumeral muscular dystrophy (FSHD) represents a majorunmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies.Wedeveloped a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response and cell adhesion. This cellularmodelwill be a powerful tool for studying FSHDandwill ultimately assist in the development of effective treatments for muscular dystrophies.

21

Caron L, Kher D, Lee KL, McKernan R, Dumevska B, Hidalgo A, Li J, Yang H, Main H, Ferri G, Petek LM, Poellinger L, Miller DG, Gabellini D, Schmidt U