Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of
DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target
genes, we over-expressed DUX4 in myoblasts and found that the receptor
tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD.
RET is dynamically expressed during myogenic progression in mouse and human
myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast
proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic
differentiation. Suppressing RET activity using Sunitinib, a clinically-
approved tyrosine kinase inhibitor, rescued differentiation in both
DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts.
Importantly, Sunitinib also increased engraftment and differentiation of FSHD
myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret
prevents myogenic differentiation and could contribute to FSHD pathology by
preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by
Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors
for treatment of FSHD