Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Moyle, Louise A.; Blanc, Eric; Jaka, Oihane; Prueller, Johanna; Banerji, Christopher R. S.; Tedesco, Francesco Saverio; Harridge, Stephen D. R.; Knight, Rob; Zammit, Peter S.

doi:10.7554/elife.11405

Cited by 18 publications

(22 citation statements)

References 110 publications

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“…Upon isolation, satellite cells activate and over time become committed myoblasts that are proliferative and able to further differentiate and fuse to form or repair muscle fibers. A previous publication [42] demonstrated that treating myoblasts with the RTK inhibitor sunitinib promoted the cells' differentiation capacity in a model of facioscapulohumeral muscular dystrophy (FSHD) [42]. As our data show that sunitinib and CEP-701 can both increase satellite cell numbers in vitro (Fig.…”

Section: Cep-701 Treatment Enhances Differentiation Of Committed Myobsupporting

confidence: 64%

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

et al. 2020

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Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential.

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Section: Cep-701 Treatment Enhances Differentiation Of Committed Myobsupporting

confidence: 64%

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

et al. 2020

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“…Interestingly, GDNF appeared significantly down-regulated in FSHD biopsies in at least two reports [ 127 , 128 ]. Another study suggests instead that FSHD involves enhanced Ret signaling in myoblasts and proposes Ret inhibitors as a possible therapeutic strategy [ 129 ]. In view of these reports and together with our present findings, it may be relevant to determine whether and to what extent modulation of GDNF/Ret signaling, or of other mechanisms influenced by Fat1 signaling, can have any benefit to alleviate adult muscle symptoms and improve quality of life of FSHD patients.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Helmbacher

2018

PLoS Biol

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Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissue-specific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation but tightly associated with elongating axons of its partner MNs. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool. Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets, including the CM-innervating pool. We identify mesenchyme-derived connective tissue (CT) as a cell type in which Fat1 activity is required for the non–cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types.

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“…Mutations in CRYM have been found to cause hearing loss [86], potentially explaining the occurrence of this phenotype in some FSHD patients. Finally, DUX4 induces the expression of the RET receptor tyrosine kinase (RTK) gene, which promotes the proliferation of satellite cell-derived myoblasts and maintains them in an undifferentiated state [87]. Treatment with sunitinib, an RTK inhibitor, inhibited Ret signalling and rescued differentiation in both mouse myoblasts expressing DUX4 and FSHD patient-derived myoblasts.…”

Section: Muscle Developmentmentioning

confidence: 99%

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

Lim

Nguyen

Yokota

2020

IJMS

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Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD.

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Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Cited by 18 publications

References 110 publications

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

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