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Gain-of-function dynamin-2 mutations linked to centronuclear myopathy impair ca2+-induced exocytosis in human myoblasts

dc.contributor.authorBayonés, Lucas
dc.contributor.authorGuerra-Fernández, María José
dc.contributor.authorHinostroza, Fernando
dc.contributor.authorBáez-Matus, Ximena
dc.contributor.authorVásquez-Navarrete, Jacqueline
dc.contributor.authorGallo, Luciana I
dc.contributor.authorParra, Sergio
dc.contributor.authorMartínez, Agustín D.
dc.contributor.authorGonzález-Jamett, Arlek
dc.contributor.authorMarengo, Fernando D.
dc.contributor.authorCárdenas, Ana M.
dc.date.accessioned2022-10-24T13:37:25Z
dc.date.available2022-10-24T13:37:25Z
dc.date.issued2022
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/4124
dc.description.abstractGain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as a reporter of the GLUT4 vesicle trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 µM ionomycin, indicating that in addition to impairing exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceInternational Journal of Molecular Sciences, 23(18), 10363es_CL
dc.subjectDynamin;es_CL
dc.subjectDynamin-2 mutationses_CL
dc.subjectCentronuclear myopathyes_CL
dc.subjectEndocytosises_CL
dc.subjectExocytosises_CL
dc.subjectGLUT4es_CL
dc.subjectPHluorines_CL
dc.subjectIRAPes_CL
dc.titleGain-of-function dynamin-2 mutations linked to centronuclear myopathy impair ca2+-induced exocytosis in human myoblastses_CL
dc.typeArticlees_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.doidoi.org/10.3390/ijms231810363es_CL


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