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...
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2017-07-01
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doaj-9c9e6b6e323144c598b2710c661215772020-12-08T01:44:30ZengNature Publishing GroupScientific Reports2045-23222017-07-017111610.1038/s41598-017-04418-wDynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cellsArlek M. González-Jamett0Ximena Baez-Matus1María José Olivares2Fernando Hinostroza3Maria José Guerra-Fernández4Jacqueline Vasquez-Navarrete5Mai Thao Bui6Pascale Guicheney7Norma Beatriz Romero8Jorge A. Bevilacqua9Marc Bitoun10Pablo Caviedes11Ana M. Cárdenas12Centro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoUniversité Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in MyologyINSERM, UMR_S1166, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN)Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in MyologyPrograma de Anatomía y Biología del Desarrollo, ICBM, Facultad de Medicina, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Universidad de ChileResearch Center for Myology, UPMC Univ Paris 06 and INSERM UMRS 974, Institute of MyologyPrograma de Farmacología Molecular y Clinica, ICBM, Facultad de Medicina, Universidad de ChileCentro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de ValparaísoAbstract 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.https://doi.org/10.1038/s41598-017-04418-w |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
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. |
url |
https://doi.org/10.1038/s41598-017-04418-w |
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