Abstract
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.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent myopathy, affecting 12/100,000 people (Deenen et al, 2014)
Co-immunolabelling to detect Pax7 and Ret51 of fixed myofibres at T0 and T24 revealed that Ret51 was barely detectable in quiescent satellite cells, but expression increased after 24 hr of activation (Figure 1A and B)
We report that Ret is a novel mediator of muscle stem cell function, is regulated by DUX4 and contributes to the pathogenic phenotype of FSHD
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent myopathy, affecting 12/100,000 people (Deenen et al, 2014). Clinical severity is highly variable, skeletal muscle weakness often appears first in the facial and shoulder girdle muscles, with muscles of the trunk and lower extremities becoming affected as the disease progresses. Analysis of myoblasts from FSHD patients has revealed direct functional impairments, including increased susceptibility to oxidative stress (Winokur et al, 2003a, 2003b; Celegato et al, 2006; Macaione et al, 2007; Barro et al, 2010), up-regulation of apoptotic markers (Winokur et al, 2003a, 2003b; Sandri et al, 2001; Vanderplanck et al, 2011; Laoudj-Chenivesse et al, 2005) and repression of MYOD and MYODtarget genes (Winokur et al, 2003b; Celegato et al, 2006).
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