Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells

Abstract Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Arlek M. González-Jamett, Ximena Baez-Matus, María José Olivares, Fernando Hinostroza, Maria José Guerra-Fernández, Jacqueline Vasquez-Navarrete, Mai Thao Bui, Pascale Guicheney, Norma Beatriz Romero, Jorge A. Bevilacqua, Marc Bitoun, Pablo Caviedes, Ana M. Cárdenas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9c9e6b6e323144c598b2710c66121577
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9c9e6b6e323144c598b2710c66121577
record_format	dspace
spelling	oai:doaj.org-article:9c9e6b6e323144c598b2710c661215772021-12-02T11:53:07ZDynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells10.1038/s41598-017-04418-w2045-2322https://doaj.org/article/9c9e6b6e323144c598b2710c661215772017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04418-whttps://doaj.org/toc/2045-2322Abstract Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.Arlek M. González-JamettXimena Baez-MatusMaría José OlivaresFernando HinostrozaMaria José Guerra-FernándezJacqueline Vasquez-NavarreteMai Thao BuiPascale GuicheneyNorma Beatriz RomeroJorge A. BevilacquaMarc BitounPablo CaviedesAna M. CárdenasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
description	Abstract Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.
format	article
author	Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas
author_facet	Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas
author_sort	Arlek M. González-Jamett
title	Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
title_short	Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
title_full	Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
title_fullStr	Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
title_full_unstemmed	Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
title_sort	dynamin-2 mutations linked to centronuclear myopathy impair actin-dependent trafficking in muscle cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9c9e6b6e323144c598b2710c66121577
work_keys_str_mv	AT arlekmgonzalezjamett dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT ximenabaezmatus dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT mariajoseolivares dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT fernandohinostroza dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT mariajoseguerrafernandez dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT jacquelinevasqueznavarrete dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT maithaobui dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT pascaleguicheney dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT normabeatrizromero dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT jorgeabevilacqua dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT marcbitoun dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT pablocaviedes dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT anamcardenas dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells
_version_	1718394881981808640

Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells

Ejemplares similares