Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy
Copyright policy )Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy
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 kinaseRetwas significantly up-regulated, suggesting a role in FSHD.RETis dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of eitherRET9orRET51increased myoblast proliferation, whereas siRNA-mediated knockdown ofRetinduced 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 ofRetprevents 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.
- Randall Division of Cell and Molecular Biophysics United Kingdom
- University College London United Kingdom
- Freie Universität Berlin Germany
- University of Toronto Canada
- Berlin Institute of Health at Charité Germany
Life Sciences & Biomedicine - Other Topics, medicine, Biomedical and clinical sciences, Indoles, Facioscapulohumeral, DUX4, Facioscapulohumeral Muscular Dystrophy, Medical Physiology, Gene Expression, MYOGENIC DIFFERENTIATION, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Myoblasts, Mice, cell biology, Sunitinib, 2.1 Biological and endogenous factors, Muscular Dystrophy, Aetiology, OXIDATIVE STRESS, Biology (General), Enzyme Inhibitors, Cells, Cultured, Cultured, Muscles, Q, R, human biology, 600, Cell Differentiation, Muscular Dystrophy, Facioscapulohumeral, Satellite Cells, Biological sciences, 5.1 Pharmaceuticals, SKELETAL-MUSCLE, Medicine, Stem Cell Research - Nonembryonic - Non-Human, Development of treatments and therapeutic interventions, Life Sciences & Biomedicine, 570, Skeletal Muscle, Satellite Cells, Skeletal Muscle, QH301-705.5, Intellectual and Developmental Disabilities (IDD), Cells, Science, Clinical Sciences, facioscapulohumeral muscular dystrophy, 610, MICE LACKING, Rare Diseases, ENTERIC NERVOUS-SYSTEM, Clinical Research, SATELLITE CELLS, Animals, Humans, Pyrroles, human, Biology, mouse, FSHD CANDIDATE GENE, Cell Proliferation, Homeodomain Proteins, FSHD, therapy, Science & Technology, Biomedical and Clinical Sciences, FAMILY-RECEPTOR, Proto-Oncogene Proteins c-ret, Health sciences, Cell Biology, Stem Cell Research, FACTOR-RECEPTOR RET, Brain Disorders, Orphan Drug, Cardiovascular and Metabolic Diseases, Musculoskeletal, Biochemistry and Cell Biology, RET, NEUROTROPHIC FACTOR
Life Sciences & Biomedicine - Other Topics, medicine, Biomedical and clinical sciences, Indoles, Facioscapulohumeral, DUX4, Facioscapulohumeral Muscular Dystrophy, Medical Physiology, Gene Expression, MYOGENIC DIFFERENTIATION, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Myoblasts, Mice, cell biology, Sunitinib, 2.1 Biological and endogenous factors, Muscular Dystrophy, Aetiology, OXIDATIVE STRESS, Biology (General), Enzyme Inhibitors, Cells, Cultured, Cultured, Muscles, Q, R, human biology, 600, Cell Differentiation, Muscular Dystrophy, Facioscapulohumeral, Satellite Cells, Biological sciences, 5.1 Pharmaceuticals, SKELETAL-MUSCLE, Medicine, Stem Cell Research - Nonembryonic - Non-Human, Development of treatments and therapeutic interventions, Life Sciences & Biomedicine, 570, Skeletal Muscle, Satellite Cells, Skeletal Muscle, QH301-705.5, Intellectual and Developmental Disabilities (IDD), Cells, Science, Clinical Sciences, facioscapulohumeral muscular dystrophy, 610, MICE LACKING, Rare Diseases, ENTERIC NERVOUS-SYSTEM, Clinical Research, SATELLITE CELLS, Animals, Humans, Pyrroles, human, Biology, mouse, FSHD CANDIDATE GENE, Cell Proliferation, Homeodomain Proteins, FSHD, therapy, Science & Technology, Biomedical and Clinical Sciences, FAMILY-RECEPTOR, Proto-Oncogene Proteins c-ret, Health sciences, Cell Biology, Stem Cell Research, FACTOR-RECEPTOR RET, Brain Disorders, Orphan Drug, Cardiovascular and Metabolic Diseases, Musculoskeletal, Biochemistry and Cell Biology, RET, NEUROTROPHIC FACTOR
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