Receptor tyrosine kinase inhibitors: a potential therapeutic strategy for FSHD?

 

Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, the authors over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase (RTK) Ret was significantly up-regulated, suggesting a role in FSHD. They demonstrate that Ret is a novel mediator of satellite cell function, contributing to the regulation of proliferation and initiation of myogenic differentiation. Critically, DUX4-mediated Ret signalling is pathogenic to satellite cells, contributing to impaired differentiation. However, blocking DUX4-mediated Ret signalling using siRNA or the clinically-approved RTK inhibitor sunitinib, leads to an increase in the myogenic capacity of DUX4-expressing murine satellite cells. Importantly, sunitinib also improves proliferation and differentiation in FSHD patient-derived myoblasts both in vitro, and in vivo after grafting into regenerating muscle in mice. 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.

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Moyle LA, Blanc E, Jaka O, et al. Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy. Elife. 2016 Nov 14;5. pii: e11405.