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Barzilai-Tutsch, H., Department of Animal Sciences, Hebrew University of Jerusalem, PO Box 12, Rehovot, 76100, Israel; Dewulf, M., Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, INSERM U1143, Centre National de la Recherche Scientifique, UMR 3666, Paris, France; Lamaze, C., Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, INSERM U1143, Centre National de la Recherche Scientifique, UMR 3666, Paris, France; Browne, G.B., Center for Research in Myology, CNRS FRE 3617, UPMC Univ Paris 06, UM76, INSERM U974, Sorbonne Universités, Paris, France; ; Halevy, O., Department of Animal Sciences, Hebrew University of Jerusalem, PO Box 12, Rehovot, 76100, Israel

In the absence of dysferlin, skeletal muscle cells fail to reseal properly after injury, resulting in slow progress of the dysferlinopathy muscular dystrophy (MD). Halofuginone, a leading agent in preventing fibrosis in MDs, was tested for its effects on membrane resealing post-injury. A hypo-osmotic shock assay on myotubes derived from wild-type (Wt) and dysferlin-null (dysf-/-) mice revealed that pre-treatment with halofuginone reduces the percentage of membrane-ruptured myotubes only in dysf-/- myotubes. In laser-induced injury of isolated myofibers, halofuginone decreased the amount of FM1-43 at the injury site of dysf-/- myofibers while having no effect on Wt myofibers. These results implicate halofuginone in ameliorating muscle-cell membrane integrity in dysf-/- mice. Halofuginone increased lysosome scattering across the cytosol of dysf-/- primary myoblasts, in a protein kinase/extracellular signal-regulated protein kinase and phosphoinositide 3 kinase/Akt-dependent manner, in agreement with an elevation in lysosomal exocytotic activity in these cells. A spatial- and age-dependent synaptotagmin-7 (Syt-7) expression pattern was shown in dysf-/- versus Wt mice, suggesting that these pattern alterations are related to the disease progress and that sytnaptotagmin-7 may be compensating for the lack of dysferlin at least with regard to membrane resealing post-injury. While halofuginone did not affect patch-repair-complex key proteins, it further enhanced Syt-7 levels and its spread across the cytosol in dysf-/- myofibers and muscle tissue, and increased its colocalization with lysosomes. Together, the data imply a novel role for halofuginone in membrane-resealing events with Syt-7 possibly taking part in these events. © The Author(s) 2018.

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A promotive effect for halofuginone on membrane repair and synaptotagmin-7 levels in muscle cells of dysferlin-null mice
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Barzilai-Tutsch, H., Department of Animal Sciences, Hebrew University of Jerusalem, PO Box 12, Rehovot, 76100, Israel; Dewulf, M., Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, INSERM U1143, Centre National de la Recherche Scientifique, UMR 3666, Paris, France; Lamaze, C., Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, INSERM U1143, Centre National de la Recherche Scientifique, UMR 3666, Paris, France; Browne, G.B., Center for Research in Myology, CNRS FRE 3617, UPMC Univ Paris 06, UM76, INSERM U974, Sorbonne Universités, Paris, France; ; Halevy, O., Department of Animal Sciences, Hebrew University of Jerusalem, PO Box 12, Rehovot, 76100, Israel

A promotive effect for halofuginone on membrane repair and synaptotagmin-7 levels in muscle cells of dysferlin-null mice

In the absence of dysferlin, skeletal muscle cells fail to reseal properly after injury, resulting in slow progress of the dysferlinopathy muscular dystrophy (MD). Halofuginone, a leading agent in preventing fibrosis in MDs, was tested for its effects on membrane resealing post-injury. A hypo-osmotic shock assay on myotubes derived from wild-type (Wt) and dysferlin-null (dysf-/-) mice revealed that pre-treatment with halofuginone reduces the percentage of membrane-ruptured myotubes only in dysf-/- myotubes. In laser-induced injury of isolated myofibers, halofuginone decreased the amount of FM1-43 at the injury site of dysf-/- myofibers while having no effect on Wt myofibers. These results implicate halofuginone in ameliorating muscle-cell membrane integrity in dysf-/- mice. Halofuginone increased lysosome scattering across the cytosol of dysf-/- primary myoblasts, in a protein kinase/extracellular signal-regulated protein kinase and phosphoinositide 3 kinase/Akt-dependent manner, in agreement with an elevation in lysosomal exocytotic activity in these cells. A spatial- and age-dependent synaptotagmin-7 (Syt-7) expression pattern was shown in dysf-/- versus Wt mice, suggesting that these pattern alterations are related to the disease progress and that sytnaptotagmin-7 may be compensating for the lack of dysferlin at least with regard to membrane resealing post-injury. While halofuginone did not affect patch-repair-complex key proteins, it further enhanced Syt-7 levels and its spread across the cytosol in dysf-/- myofibers and muscle tissue, and increased its colocalization with lysosomes. Together, the data imply a novel role for halofuginone in membrane-resealing events with Syt-7 possibly taking part in these events. © The Author(s) 2018.

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